Rak żołądka – Patofizjologia i mechanizm

Rak żołądka
Patofizjologia i mechanizm

Rak żołądka stanowi piąty najczęściej diagnozowany nowotwór i czwartą przyczynę zgonów onkologicznych na świecie. Jego patogeneza jest wieloczynnikowa, obejmująca przewlekłe zakażenie Helicobacter pylori, które odpowiada za około 60% przypadków oraz wirusa Epstein-Barr (EBV) obecnego w około 9% nowotworów żołądka. H. pylori indukuje przewlekły stan zapalny, uszkodzenia DNA oraz aktywuje kluczowe szlaki sygnałowe, takie jak JAK/STAT, NF-κB, Wnt/β-katenina, MAPK, PI3K/Akt i TGF-β, co sprzyja karcinogenezie. Zmiany genetyczne, w tym mutacje TP53 (obecne w 80% przypadków), K-ras, CDH1 oraz RHOA, a także epigenetyczne modyfikacje, takie jak aberrantna metylacja DNA i zaburzenia mikroRNA, prowadzą do niestabilności genomowej (MSI i CIN) i dysregulacji apoptozy oraz proliferacji komórek. Przewlekłe zapalenie, indukowane przez H. pylori i inne czynniki, powoduje uszkodzenia DNA i tworzy mikrośrodowisko sprzyjające progresji nowotworu.

Patogeneza raka żołądka

Rak żołądka jest schorzeniem nowotworowym stanowiącym istotny problem zdrowotny na świecie, będąc piątym najczęściej diagnozowanym nowotworem i czwartą przyczyną zgonów związanych z chorobami nowotworowymi¹². Patogeneza raka żołądka jest złożonym, wieloczynnikowym procesem, który rozwija się przez dziesięciolecia i wynika z akumulacji licznych zmian genetycznych i epigenetycznych³⁴. Te zmiany są kluczowe dla komórek nowotworowych, aby przyspieszyć i podtrzymać szereg szlaków zaangażowanych w rozwój raka, takich jak cykl komórkowy, naprawa DNA, metabolizm, interakcje komórka-komórka i komórka-macierz, apoptoza, angiogeneza i nadzór immunologiczny⁵.

Rola Helicobacter pylori w patogenezie raka żołądka

Zakażenie Helicobacter pylori jest głównym czynnikiem ryzyka rozwoju raka żołądka i zostało uznane przez Międzynarodową Agencję Badań nad Rakiem za karcynogen grupy 1⁶⁷. Najnowsze szacunki pokazują, że 89% wszystkich nowotworów nieobejmujących wpustu żołądka (około 780 000 przypadków) można przypisać zakażeniu H. pylori, co czyni tę bakterię odpowiedzialną za co najmniej 6,2% wszystkich przypadków raka na świecie⁸. Bakteria H. pylori odpowiada za ponad 60% przypadków raka żołądka⁹.

Mechanizm, przez który H. pylori indukuje raka żołądka, potencjalnie obejmuje przewlekły stan zapalny, działanie czynników wirulencji H. pylori, takich jak CagA, lub interakcję między zakażeniem H. pylori a patogennymi wariantami germinalnych genów zaangażowanych w rekombinację homologiczną¹⁰. Zakażenie H. pylori prowadzi do reakcji zapalnych poprzez różne szlaki molekularne indukowane zarówno w komórkach nabłonkowych żołądka, z którymi bakteria ma pierwszy kontakt, jak i w krążących komórkach immunologicznych rekrutowanych do miejsca zakażenia, takich jak neutrofile, makrofagi i limfocyty¹¹.

Szczepy H. pylori, które zawierają wyspę patogenności cytotoksyny związanej z genem (cag), kodującą system sekrecji typu IV (T4SS), zwiększają ryzyko rozwoju poważniejszych chorób żołądka¹². Inne ważne czynniki wirulencji H. pylori, które zwiększają progresję choroby, obejmują cytotoksynę wakuolizującą A (VacA), specyficznie allele vacA typu s1m1, proteazę serynową HtrA oraz adhezyny błony zewnętrznej HopQ, BabA, SabA i OipA¹³.

H. pylori powoduje zapalenie i prowadzi zarówno bezpośrednio, jak i pośrednio do uszkodzenia DNA w komórkach gospodarza. Ponadto powstałe zaburzenia genetyczne i/lub epigenetyczne zmieniają wybór ścieżek naprawy DNA. Te zmiany powodują nieprawidłową naprawę DNA, niestabilność genomową i aberracje chromosomalne, które ostatecznie mogą promować karcinogenezę żołądka¹⁴.

Rola wirusa Epstein-Barr w patogenezie raka żołądka

Wirus Epstein-Barr (EBV) jest uznawany za ludzki karcynogen związany z rozwojem kilku typów chłoniaków i raków, odpowiadający za około 200 000 nowych przypadków raka rocznie na całym świecie¹⁵. Około 9% przypadków raka żołądka ma utajoną infekcję EBV w każdej komórce nowotworowej¹⁶. Reaktywacja EBV z latencji jest postulowanym mechanizmem rozwoju nowotworów złośliwych związanych z EBV¹⁷.

EBV służy jako drugi główny czynnik ryzyka w karcinogenezie żołądka¹⁸. Białko wirusa, niekodujący RNA EBER i miRNA EBV przyczyniają się do tumorygenezy poprzez modulację metylacji genomu gospodarza i ekspresji genów¹⁹. EBV odpowiada za około 10% przypadków raka żołądka²⁰.

Pierwszą zagadką związaną z rakiem żołądka związanym z EBV (EBVaGC) jest to, jak EBV zakaża komórki nabłonkowe żołądka, ponieważ zakażenie EBV często występuje w limfocytach B i nabłonku jamy ustnej²¹. Wiadomo, że białka LMP1 i antygen jądrowy 2 (EBNA2) wirusa EBV odgrywają główną rolę w onkogenezie indukowanej przez EBV. Jednak obie te białka rzadko wykrywano w komórkach gruczolakoraka żołądka. Zamiast tego potwierdzono ekspresję EBNA1²².

Kluczowe szlaki molekularne w patogenezie raka żołądka

Skomplikowane sieci sygnałowe odgrywają istotną rolę w patogenezie raka żołądka. Wśród najważniejszych szlaków molekularnych można wymienić:

Szlak JAK/STAT – Kaskada JAK/STAT jest głównym szlakiem transdukcji sygnału w sygnalizacji cytokin i czynników wzrostu, regulując różne procesy komórkowe, takie jak proliferacja komórek, różnicowanie, migracja i przeżycie²³. Liczne badania in vivo i in vitro wykazały, że dysregulacja sygnalizacji JAK/STAT jest siłą napędową w patogenezie różnych guzów litych, a także nowotworów hematologicznych²⁴. Czynnik transkrypcyjny STAT3 odgrywa kluczową rolę w progresji raka żołądka stymulowanej przez H. pylori²⁵.
Szlak NF-κB – NF-κB jest kluczowym czynnikiem transkrypcyjnym w karcinogenezie żołądka inicjowanej przez H. pylori²⁶. Jest krytycznym regulatorem genów zaangażowanych w przeżycie komórek i proliferację, komórkową odpowiedź na stres i zapalenie²⁷.
Szlak Wnt/β-katenina – Szlak sygnałowy Wnt/β-katenina jest kluczowym mechanizmem regulacyjnym w raku żołądka związanym z H. pylori²⁸. Odgrywa ważną rolę w inwazji i przerzutach raka żołądka i może być dobrym wskaźnikiem do oceny biologicznego zachowania raka żołądka²⁹.
Szlak MAPK (Ras/Raf/Mek/Erk) – Szlak sygnałowy MAPK reguluje szereg aktywności komórkowych, takich jak angiogeneza, proliferacja, różnicowanie, apoptoza i migracja³⁰.
Szlak PI3K/Akt – Szlak kinazy PI3 (PI3K)/Akt reguluje metabolizm komórkowy i wzrost, działając jako komórkowy czujnik składników odżywczych i czynników wzrostu, i odgrywa ważną rolę w onkogenezie³¹.
Szlak TGF-β – We wczesnych stadiach raka żołądka sygnalizacja TGF-β jest uważana za szlak supresora nowotworów, podczas gdy w późnym stadium promuje inwazję i przerzuty³².

Zmiany genetyczne i epigenetyczne w patogenezie raka żołądka

Zmiany genetyczne, takie jak mutacje genów, amplifikacja genów, delecje lub utrata alleli i translokacje chromosomalne, mogą powodować uzyskanie funkcji w onkogenach i utratę funkcji w genach supresorów nowotworów, ostatecznie przyczyniając się do karcinogenezy żołądka³³. Ponadto, podobnie jak w przypadku innych nowotworów złośliwych u ludzi, tumorogeneza żołądka może być również głęboko uzależniona od nieprawidłowości epigenetycznych, takich jak nieprawidłowa metylacja genów, modyfikacja histonów i mikroRNA³⁴.

Zwiększona dawka genu przez to zdarzenie genetyczne jest powszechnym mechanizmem nadmiernej ekspresji onkogenów podczas tumorygenezy i odzwierciedla również niestabilność genetyczną komórek nowotworowych, podobnie jak inne rodzaje zmian genetycznych³⁵.

Aberrantna hipermetylacja wysp CpG promotora genów supresorowych nowotworów, prowadząca do ich inaktywacji, występuje na wysokim poziomie podczas zapalenia żołądka i karcinogenezy³⁶. Zakażenie H. pylori zwiększa nieprawidłową metylację promotora w błonie śluzowej żołądka, przyczyniając się do tumorygenezy żołądka poprzez wyciszanie genów supresorowych nowotworów³⁷.

Oprócz metylacji DNA, mikroRNA (miRNA) i modyfikacje histonów są ważnymi modyfikacjami epigenetycznymi, które odgrywają kluczową rolę w karcinogenezie żołądka³⁸. Te obserwacje sugerują, że miRNA i modyfikacja histonów mogą odgrywać kluczową rolę w karcinogenezie żołądka i są ściśle związane z gorszym rokowaniem u pacjentów z rakiem³⁹.

Niestabilność genetyczna w raku żołądka

Większość raków żołądka charakteryzuje się niestabilnością genetyczną, która jest ogólnie klasyfikowana na dwa główne typy: niestabilność mikrosatelitarną (MSI) i niestabilność chromosomową (CIN)⁴⁰.

W genomach stabilnych podtypach wykryto mutację RHOA⁴¹. Brak spójności komórkowej jest cechą charakterystyczną tego fenotypu rozlanego⁴².

Kolejne podtypy raka żołądka są bogate w MSI, które wykazują zwiększone wskaźniki mutacji (w genach głównego kompleksu zgodności tkankowej klasy I, w tym B2M i HLA-B) i hipermetylację (zawierającą hipermetylację w promotorze MLH1)⁴³.

Ostatnia grupa raków żołądka została sklasyfikowana jako podtyp CIN⁴⁴. Zwiększenie lub utrata całych chromosomów (aneuploidia) lub części chromosomów, utrata heterozygotyczności (LOH) i translokacje są charakterystyczne dla CIN w sporadycznych guzach żołądka⁴⁵.

Specyficzne geny w patogenezie raka żołądka

Rak żołądka jest wynikiem defektów genetycznych prowadzących do niekontrolowanego wzrostu komórek⁴⁶. Stwierdzono, że gen TP53 jest uszkodzony (zmutowany) lub utracony w nawet 80% raków żołądka⁴⁷. Jednak mutacje w tym genie są również znajdowane w 60% raków żołądka typu jelitowego i 25% gruczolaków żołądka⁴⁸.

Mutację aktywacyjną K-ras stwierdza się w inwazyjnych rakach i metaplazji jelitowej⁴⁹. Inaktywacja p53 w komórkach nabłonkowych żołądka zmniejsza ich zdolność do przechodzenia apoptozy⁵⁰. Metylacja DNA promotorów genów może wyciszyć ekspresję CDH1⁵¹.

Mutacja β-kateniny jest częstą przyczyną aktywacji szlaku Wnt w raku żołądka⁵²⁵³. β-katenina jest częścią szlaku sygnałowego Wnt, który reguluje koordynację wydarzeń, takich jak przyleganie komórek, migracja, proliferacja i różnicowanie⁵⁴. Białko genu APC zapobiega akumulacji β-kateniny. Mutacje APC prowadzą do utraty regulacji β-kateniny, co prowadzi do proliferacji, angiogenezy, inwazji nowotworów i przerzutów komórek⁵⁵.

W przypadku rodzinnego raka żołądka typu rozlanego (HDGC), zmiany germinalne w genie E-kadheryny CDH1 stanowią 30-40% tego rzadkiego zespołu⁵⁶. Inaktywacja drugiego allelu E-kadheryny poprzez mutację, metylację i utratę heterozygotyczności ostatecznie wyzwala rozwój raka żołądka⁵⁷.

W ramach badania The Cancer Genome Atlas (TCGA) zidentyfikowano cztery molekularnie odrębne podtypy raka żołądka: dodatni na wirus Epstein-Barr (EBV+), niestabilność mikrosatelitarną (MSI), stabilny genomowo i niestabilny chromosomowo (CIN)⁵⁸. Wskaźnik mutacji PIK3CA jest wyjątkowo wysoki w raku żołądka EBV-dodatnim w porównaniu z innymi podtypami molekularnymi⁵⁹.

Rola cyklooksygenazy-2 (COX-2) w patogenezie raka żołądka

Cyklooksygenaza-2 (COX-2) jest enzymem ograniczającym szybkość odpowiedzialnym za konwersję kwasu arachidonowego do prostaglandyn (PG). Jej nadekspresję odnotowano w różnych nowotworach złośliwych u ludzi, w tym w raku żołądka⁶⁰.

Innym enzymem indukowalnym o właściwościach karcynogennych, który jest aktywny w tkankach z zapaleniem i zmianami złośliwymi, jest cyklooksygenaza-2 (COX-2)⁶¹. COX-2 została opisana jako centralny mediator odpowiedzi immunologicznej i jako krytycznie zaangażowana w zapalenie związane z rakiem i odpowiedź na naprawę tkanek⁶².

Rola przewlekłego zapalenia w patogenezie raka żołądka

Przewlekła odpowiedź zapalna wywołana przez H. pylori jest znaczącym czynnikiem ryzyka karcinogenezy żołądka, obejmującym złożone interakcje z innymi procesami karcynogennymi, takimi jak stres oksydacyjny i nieprawidłowa aktywacja szlaków nowotworowych⁶³. Przewlekła odpowiedź zapalna stymulowana przez H. pylori jest krytycznym mechanizmem w karcinogenezie żołądka. Komórki zapalne i ich mediatory są zaangażowane w wiele etapów karcinogenezy żołądka, w tym uszkodzenie DNA, mutacje genów i tworzenie mikrośrodowiska guza⁶⁴.

Związek przyczynowy między zapaleniem a rakiem został dobrze rozpoznany⁶⁵. Osoba zakażona H. pylori ma większą szansę na rozwój przewlekłego zapalenia⁶⁶. H. pylori wykorzystuje czynniki wirulencji CagA, VacA i peptydoglikan do zwiększenia ekspresji cytokin prozapalnych, takich jak IL-1, IL-6, IL-8, TNF-α i NF-κB, w celu aktywacji kaskady sygnałowej NF-κB w komórkach nabłonkowych żołądka i krążących komórkach odpornościowych⁶⁷. Produkcja cytokin wyzwala aktywację i migrację leukocytów oraz kaskadę regulacyjną cytokin, chemokin i adhezji⁶⁸.

Aberrantne zmiany genetyczne gospodarza są również kluczowe dla interakcji H. pylori i komórek nabłonkowych żołądka. Polimorfizmy w IL-1 i jej endogennym antagoniście receptora wpływają na produkcję IL-1 przez błonę śluzową żołądka w odpowiedzi na zakażenie H. pylori i są związane z występowaniem raka żołądka⁶⁹.

Dezregulacja apoptozy w patogenezie raka żołądka

Deregulacja apoptozy komórek jest kluczowym wydarzeniem w karcinogenezie żołądka indukowanej przez H. pylori, a H. pylori jest zdolny do manipulowania apoptozą w komórkach nabłonkowych żołądka, aby sprzyjać przeżyciu i ekspansji guza⁷⁰. Hamowanie apoptozy jest krytycznym mechanizmem molekularnym w karcinogenezie. Przewlekłe zakażenie H. pylori i wynikający z niego stan zapalny tworzą środowisko sprzyjające tumorygenezie⁷¹.

H. pylori stosuje dodatkowe strategie przyczyniające się do rozwoju raka żołądka, w tym zakłócanie progresji cyklu komórkowego i autofagii⁷². Mechanizmy molekularne leżące u podstaw karcinogenezy promowanej przez H. pylori są wyjątkowo skomplikowane, obejmując wzajemne oddziaływanie licznych szlaków i wzajemnie powiązanych połączeń⁷³.

Dynamiczna równowaga między proliferacją komórek a apoptozą jest kluczowa dla utrzymania homeostazy śluzówki. Zmniejszona apoptoza, jak również zwiększona proliferacja mogą sprzyjać procesowi karcynogennemu. Przedłużone przeżycie nieprawidłowych komórek może wspierać akumulację sekwencyjnych mutacji genetycznych, zmiany w profilach ekspresji genów oraz strukturze i funkcji białek, co może skutkować promocją guza żołądka⁷⁴.

Rola mikroflory żołądkowej w patogenezie raka żołądka

Mikroflora żołądkowa odgrywa ważną rolę w patogenezie raka żołądka. Niedawne badania wykazały, że Streptococcus anginosus konsekwentnie obserwuje się w biopsjach błony śluzowej pacjentów z rakiem żołądka z wielu badań. Mechanistycznie, nasze poprzednie badanie wykazało, że S. anginosus produkuje cytokiny prozapalne, w tym Ccl20 i Ccl8, aby wywołać ostre zapalenie w żołądku⁷⁵.

Badacze zidentyfikowali mechanizm działania bakterii S. anginosus i stwierdzili, że używa ona swojego białka powierzchniowego, TMPC, do komunikacji z receptorem Annexin A2 (ANXA2) na komórkach wyściełających żołądek. Interakcja pozwala bakteriom przyłączyć się do komórki i kolonizować ją, aktywując kinazę białkową aktywowaną mitogenem (MAPK), enzym, który koordynuje proliferację, różnicowanie i przeżycie komórek⁷⁶.

Grzybicza dysbioza w raku żołądka charakteryzuje się zwiększoną obfitością Cutaneotrichosporon, Malassezia, Solicoccozyma i Archaeorhizomyces w dwóch niezależnych kohortach chińskich⁷⁷.

Kaskada Correi w patogenezie raka żołądka

Kaskada Correi opisuje klasyczną sekwencję zmian histologicznych dla najczęstszego raka żołądka: gruczolakoraka typu jelitowego. Została ona po raz pierwszy opisana w 1975 roku, ale później powiązana z zakażeniem H. pylori po zidentyfikowaniu go jako przyczyny zapalenia żołądka w 1983 roku⁷⁸. Sekwencja postępuje od normalnej błony śluzowej żołądka do dysplazji żołądka, która charakteryzuje się wysokim ryzykiem rozwoju inwazyjnego raka⁷⁹.

Rak żołądka rozwija się poprzez złożony wieloetapowy proces, w którym błona śluzowa żołądka powoli przekształca się z normalnej w przewlekłe zapalenie żołądka, wieloogniskowy zanik, metaplazję jelitową o różnych stopniach, dysplazję, a następnie inwazyjny rak⁸⁰. Proces jest najwyraźniej napędzany przez siły działające na nabłonek żołądka przez wiele lat, takie jak nadmierny poziom soli w diecie i, najczęściej, zakażenie Helicobacter pylori⁸¹.

Długotrwałe przewlekłe powierzchowne zapalenie żołądka spowodowane przewlekłym zakażeniem H. pylori, niedokrwistością złośliwą lub prawdopodobnie dietą z wysoką zawartością soli prowadzi ostatecznie do przewlekłego zanikowego zapalenia żołądka i metaplazji jelitowej⁸². Zanikowi żołądka towarzyszy utrata masy komórek okładzinowych, a tym samym zmniejszenie produkcji kwasu (hipochlorhydria lub achlorhydria), zmniejszenie poziomu kwasu askorbinowego (witaminy C) w świetle przewodu pokarmowego oraz kompensacyjny wzrost poziomu gastryny w surowicy, silnego induktora proliferacji komórek nabłonkowych żołądka⁸³.

Patogeneza raka żołądka typu rozlanego

Raki rozlane żołądka nie mają zmiany przedrakowej⁸⁴. Są one wysoce przerzutowe, z gorszym rokowaniem niż raki typu jelitowego⁸⁵. Komórki nowotworowe tego typu tracą spójność i pierwotną funkcję⁸⁶. W porównaniu z typem jelitowym, jego patogeneza jest znacznie mniej zbadana⁸⁷.

Gdy cała ściana żołądka jest nacieczona, powoduje to sztywną, pogrubiałą ścianę żołądka zwaną linitis plastica⁸⁸. Somatyczne mutacje w genie CDH1 przez hipermetylację, mutację i utratę heterozygotyczności są identyfikowane w 40-83 procentach sporadycznych raków żołądka typu rozlanego⁸⁹.

Kluczowym mechanizmem w raku żołądka typu rozlanego jest utrata białka zwanego E-kadheryną. E-kadheryna odpowiada za adhezję komórkową, pomagając komórkom przylegać do siebie. Utrata E-kadheryny prowadzi do dysocjacji komórek. Ta utrata może wystąpić z powodu mutacji w genie supresora nowotworu zwanym cdh1, który koduje E-kadherynę. Dodatkowo, hipermetylacja i wyciszenie regionu promotora cdh1 mogą również prowadzić do utraty E-kadheryny⁹⁰.

Utrata E-kadheryny w raku żołądka typu rozlanego powoduje naciekanie komórek nowotworowych przez całą ścianę żołądka. To naciekanie wywołuje odpowiedź desmoplastyczną, prowadzącą do usztywnienia ściany żołądka⁹¹. Dotknięte obszary wykazują rozlane spłaszczenie fałdów śluzówki i sztywny, pogrubiały wygląd przypominający skórzaną butelkę (linitis plastica) w badaniach obrazowych⁹².

Rak żołądka typu rozlanego (DGC) jest wyraźną histopatologiczną i molekularną chorobą, charakteryzującą się mutacjami w CDH1, RHOA i innych⁹³. Zrozumienie genetycznych i molekularnych podstaw DGC może pomóc w zrozumieniu jego zachowania klinicznego i pomóc w badaniach przesiewowych, diagnozie i odpowiedzi na leczenie⁹⁴.

Etiologia DGC jest zróżnicowana⁹⁵. Oprócz etiologii środowiskowych, somatyczne i germinalne mutacje w wielu genach mogą przyczynić się do rozwoju DGC⁹⁶. Około 13% wszystkich raków żołądka jest spowodowanych dziedzicznym rozlanym rakiem żołądka (HDGC), z czego 40% jest związanych z mutacjami germinalnymi w CDH1⁹⁷.

Najczęstsze mutacje CDH1 to mutacje skracające lub przewidywane jako szkodliwe mutacje zmiany sensu w domenie kadheryny, występujące 2,5 razy częściej u osób z fenotypem komórek sygnetowatych i przewidywane jako związane z utratą funkcji⁹⁸. We wszystkich przypadkach mutacje CDH1 były klonalne i współwystępowały z mutacjami w TP53, innym ważnym genie supresora nowotworów, co sugeruje, że mutacja ta jest nabywana wcześnie w patogenezie choroby⁹⁹.

Rola mikrootoczenia guza w patogenezie raka żołądka

Mikrootoczenie guza (TME) składa się z wielu elementów, takich jak fibroblasty podścieliska guza, limfocyty i czynniki angiogenne. Wszystkie te składniki współpracują ze sobą, tworząc kontekst dla rozwoju raka żołądka¹⁰⁰.

TME raka żołądka wykazuje dużą plastyczność i podlega ciągłym zmianom i modyfikacjom specyficznym dla stadium w odpowiedzi na różne wewnętrzne i zewnętrzne czynniki związane z komórkami nowotworowymi. Sieci cytokin i czynników wzrostu zakłócają szlaki sygnałowe, a zmodyfikowane sygnatury molekularne w podścielisku charakteryzują te zmiany w TME¹⁰¹.

Fibroblasty związane z rakiem (CAF) są głównym źródłem podścieliska i wydzielają czynniki rozpuszczalne, takie jak chemokiny, cytokiny i czynniki wzrostu, aby zatrudnić różne typy komórek do TME i przeprogramować je. CAF produkują również ligandy zapalne i białka macierzy zewnątrzkomórkowej, co z kolei promuje wzrost guza, inwazję i migrację komórek nowotworowych, a także ucieczkę immunologiczną i oporność na terapie przeciwnowotworowe¹⁰².

Podczas progresji guza, CAF promują wydzielanie kluczowych białek strukturalnych, w tym kolagenu typu I-V i elastyny, które uczestniczą w tworzeniu błony podstawnej (BM), zapaleniu i angiogenezie¹⁰³. Zaobserwowano, że enzym podobny do oksydazy lizylowej 2 (LOXL2), który katalizuje sieciowanie ECM w celu utworzenia stabilnego kolagenu I, był coraz bardziej wydzielany przez żołądkowe CAF w porównaniu z normalnymi fibroblastami żołądka. LOX2 aktywował szlak FAK/Src, prowadząc do zwiększonej migracji i inwazji komórek raka żołądka¹⁰⁴.

Aktywacja sygnalizacji TGF-β regulowanej przez TGFBR3 była wywołana przez zewnątrzkomórkową sulfatazę, ludzką sulfatazę 1, wydzielaną przez CAF. Ta interakcja powoduje również promocję przejścia nabłonkowo-mezenchymalnego (EMT), oporność na chemioterapię w komórkach raka żołądka i przerzuty za pośrednictwem sygnalizacji TGF-β¹⁰⁵.

Rola zakwaszenia w rozwoju raka żołądka

Zewnętrzne zakwaszenie, charakterystyczna cecha guzów litych, zostało zaproponowane jako krytyczny czynnik zaostrzający złośliwość guza i nadający oporność na leki terapeutyczne¹⁰⁶. Niedawno parametry metaboliczne tkanek nowotworowych, takie jak zewnętrzne zakwaszenie, zostały zaproponowane jako krytyczne dla złośliwości guza i oporności na leki terapeutyczne¹⁰⁷. Taka kwasica sprawozdano nadaje nieskuteczne środowisko terapeutyczne prowadzące do selekcji bardziej opornych i agresywnych cech¹⁰⁸.

Jednak mechanizmy, przez które kwaśne środowisko pH wywołuje oporność w komórkach nowotworowych, nie są dobrze poznane¹⁰⁹. Kwaśne warunki hodowli zwiększały aktywność PLA2 w komórkach raka żołądka¹¹⁰. Dlatego enzymy PLA2 wydają się być aktywowane lub regulowane w górę w kwaśnych warunkach pH w tych komórkach¹¹¹.

Ponieważ kwaśne warunki pH zwiększały aktywność PLA2 w komórkach raka żołądka, zbadano, czy kwasowość wpływa na ekspresję komórkowych enzymów PLA2¹¹². Wynik ten wskazuje, że kwaśne warunki pH zwiększają ekspresję cPLA2 zarówno w komórkach raka żołądka SNU601, jak i AGS¹¹³. Dlatego zwiększona ekspresja cPLA2 może odgrywać rolę w ochronie komórek SNU601 przed cytotoksycznym efektem wywołanym przez kwaśne środowisko¹¹⁴.

Tak więc, wzrost ekspresji cPLA2 wydaje się być zaangażowany w oporność na leki przeciwnowotworowe pośredniczoną przez kwasowość poprzez zmniejszenie apoptozy komórek nowotworowych¹¹⁵. Podsumowując, na podstawie ustaleń niniejszego badania, sugerujemy, że cPLA2 może być ważnym celem terapeutycznym dla opornych komórek nowotworowych w kwaśnym środowisku¹¹⁶.

Zmiany metaboliczne w patogenezie raka żołądka

Rak żołądka jest jednym z najbardziej złośliwych nowotworów na świecie, a jego mechanizm patologiczny jest generalnie nieznany¹¹⁷. W ostatnich dziesięcioleciach badania mające na celu zakażenie Helicobacter pylori, podatność dziedziczną i czynniki środowiskowe dokonały wielkiego przełomu w badaniu jego precyzyjnej patogenezy¹¹⁸.

Ostatnio zastosowanie różnych technologii „-omics” otworzyło nowe pole do badania mechanizmów leżących u podstaw tej choroby¹¹⁹. Wraz z powstaniem metabolomiki poczyniono znaczne postępy w zrozumieniu związku między regulacją metaboliczną a rakiem¹²⁰. Rozległe badania wskazują również, że przeprogramowanie metaboliczne jest jedną z cech charakterystycznych raka i jest skomplikowanie powiązane z onkogenezą i ucieczką immunologiczną raka¹²¹.

Do tej pory przeprowadzono kilka badań mających na celu zidentyfikowanie identyfikowalnych zmian metabolicznych w makrośrodowisku – krwi i moczu lub mikrośrodowisku – tkankach rakowych i soku żołądkowym, aby globalnie zmapować profile metaboliczne i zinterpretować jego możliwy mechanizm w procesie karcinogenezy żołądka¹²².

Zmienione metabolity w żołądku można podzielić na cztery główne biomolekuły: węglowodany, aminokwasy, lipidy i kwasy nukleinowe¹²³. Aktywowana glikoliza i zaburzone oddychanie tlenowe kształtują zmieniony metabolizm glukozy w tej chorobie¹²⁴. Podwyższone aminokwasy w mikrośrodowisku są czynnikami przyczyniającymi się do karcinogenezy¹²⁵.

Co najbardziej uderzające, wskazuje się, że wiele linii komórek nowotworowych nie może przetrwać w przypadku braku glutaminy, ponieważ jest ona wymagana do anabolicznego wzrostu komórek ssaczych dzięki jej zdolności do kontrolowania głównego regulatora translacji białek mTORC1¹²⁶. Przeprogramowanie metabolizmu glutaminy dodatkowo przyczynia się do proliferacyjnych i metabolicznych odpowiedzi regulowanych przez onkogenny czynnik transkrypcyjny c-MYC¹²⁷.

Godną uwagi cechą metabolizmu lipidów w komórkach nowotworowych jest zwiększona szybkość lipogenezy i zwiększenie regulacji mitochondrialnego β-utleniania kwasów tłuszczowych, rak żołądka wykazuje podobną tendencję i przedstawia typowe zmiany dotyczące różnych metabolitów zaangażowanych w metabolizm lipidów¹²⁸.

Rola komórek macierzystych w patogenezie raka żołądka

W odniesieniu do patogenezy warto wspomnieć o dwóch nowych koncepcjach: udziale szpiku kostnego w karcinogenezie żołądka i komórkach macierzystych raka żołądka. Postawiono hipotezę, że komórki nabłonkowe żołądka nabywające nieprawidłowy fenotyp (przypominający nabłonek jelitowy) pochodzą z komórek macierzystych żołądka zlokalizowanych w jedynej strefie replikacji komórek gruczołów żołądkowych (tj. przewężku)¹²⁹.

Chociaż jest to kontrowersyjne, komórki macierzyste raka są definiowane jako komórki nowotworowe z wyłączną zdolnością do inicjowania guzów, przerzutów i samoodnowy guzów. W raku żołądka kilku badaczy zasugerowało istnienie komórek macierzystych raka żołądka (tj. CD44+) i komórek populacji bocznej. Komórki te wykazywały względną oporność na chemioterapię i promieniowanie oraz wyłączną zdolność do inicjowania guzów¹³⁰.

Rak żołądka jest jedną z najczęstszych przyczyn zgonów związanych z rakiem na świecie. Główną przyczyną tego raka jest bakteria Helicobacter pylori, która przewlekle zakaża około połowę wszystkich ludzi¹³¹. Multidyscyplinarny zespół badawczy w Instytucie Maxa Plancka w Berlinie we współpracy z badaczami ze Stanford w Kalifornii odkrył, że bakteria wysyła odnowę komórek macierzystych w żołądku do nadmiernej aktywności, a obrót komórek macierzystych był podejrzewany przez wielu naukowców o odgrywanie roli w rozwoju raka¹³².

Podejrzewali, że odpowiedź może tkwić w komórkach macierzystych znajdujących się na dnie gruczołów wyściełających wnętrze żołądka, które ciągle zastępują pozostałe komórki od dołu do góry i które są jedynymi długo żyjącymi komórkami w żołądku¹³³. Odkryli teraz, że te komórki macierzyste rzeczywiście reagują na infekcję, zwiększając swój podział, produkując więcej komórek i prowadząc do charakterystycznego pogrubienia błony śluzowej obserwowanego u chorych pacjentów¹³⁴.

Kluczowo, odkryli, że komórki miofibroblastowe w warstwie tkanki łącznej bezpośrednio pod gruczołami produkują drugi sygnał sterownika komórek macierzystych, R-spondin, na który dwie populacje komórek macierzystych reagowały różnie¹³⁵. To właśnie ten sygnał, jak się okazało, kontroluje odpowiedź na H. pylori: Po zakażeniu, sygnał jest zwiększany, wyciszając wolniej cykliczną populację komórek macierzystych i wprowadzając szybciej cykliczną populację komórek macierzystych do nadmiernej aktywności¹³⁶.

Mechanizmy patogenezy raka żołądka – podsumowanie

Patogeneza raka żołądka to złożony, wieloczynnikowy proces obejmujący:

Zakażenie Helicobacter pylori, które powoduje przewlekłe zapalenie, uszkodzenia DNA i wprowadza czynniki wirulencji (CagA, VacA)¹³⁷¹³⁸
Zakażenie wirusem Epstein-Barr (EBV) w około 9% przypadków, z charakterystycznym profilem molekularnym¹³⁹
Zaburzenia w kluczowych szlakach sygnałowych: JAK/STAT, NF-κB, Wnt/β-katenina, MAPK, PI3K/Akt, TGF-β¹⁴⁰
Zmiany genetyczne: mutacje, amplifikacje, delecje genów (TP53, K-ras, CDH1, RHOA)¹⁴¹
Zmiany epigenetyczne: nieprawidłowa metylacja DNA, modyfikacje histonów, zaburzenia w mikroRNA¹⁴²
Niestabilność genetyczną: niestabilność mikrosatelitarną (MSI) i niestabilność chromosomową (CIN)¹⁴³
Zaburzenia apoptozy i proliferacji komórkowej¹⁴⁴
Przewlekłe zapalenie prowadzące do uszkodzeń DNA i zmian genetycznych¹⁴⁵
Zmiany w mikrośrodowisku guza z udziałem fibroblastów, komórek immunologicznych i naczyniowych¹⁴⁶
Zmiany metaboliczne obejmujące metabolizm glukozy, aminokwasów i lipidów¹⁴⁷
Dysregulację komórek macierzystych w żołądku pod wpływem infekcji H. pylori¹⁴⁸

Te mechanizmy odpowiadają za progresję od zdrowej błony śluzowej żołądka, przez etapy przedrakowe (zapalenie, zanik, metaplazja jelitowa, dysplazja), do inwazyjnego raka. W przypadku raka typu rozlanego kluczową rolę odgrywa utrata funkcji E-kadheryny, co prowadzi do utraty spójności komórkowej i agresywnego fenotypu¹⁴⁹.

Zrozumienie tych złożonych, wzajemnie powiązanych szlaków molekularnych stanowi podstawę dla opracowania nowych strategii diagnostycznych, prognostycznych i terapeutycznych w raku żołądka¹⁵⁰.

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Materiały źródłowe

#1 Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms
https://www.mdpi.com/1422-0067/24/3/2895
Gastric cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Helicobacter pylori (H. pylori) is one of the main risk factors for this type of neoplasia. Carcinogenetic mechanisms associated with H. pylori are based, on the one hand, on the onset of chronic inflammation and, on the other hand, on bacterial-specific virulence factors that can damage the DNA of gastric epithelial cells and promote genomic instability. Here, we review and discuss the major pathogenetic mechanisms by which H. pylori infection contributes to the onset and development of gastric cancer. […] H. pylori infection induces chronic non-atrophic gastritis that can progress to intestinal metaplasia, dysplasia, and finally gastric cancer. […] In this sequential process, both the chronic inflammatory response and the presence of specific bacterial virulence factors, especially the cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), play a fundamental role in causing damage to host cell DNA and in the activation of specific pathways that sustain cell survival, with both processes often supporting each other.
#2
https://www.alliedacademies.org/articles/short-description-of-molecular-pathogenesis-of-gastric-cancer-23296.html
Gastric Cancer (GC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. […] Helicobacter pylori infection, smoked and fried food, diets low in fruit and vegetables, high salt intake, geographical location, genetic factors, age, and sex are considered risk factors for the development of stomach cancer. […] Approximately, 10% of patients with gastric cancer show familial aggregation and 13% of them have germline mutations. […] In addition to histological classification of gastric cancer genome-wide analyses of DNA copy number alterations, mutations, mRNA, miRNA, and protein patterns proposes four molecularly distinct gastric cancer subtypes categorised as Epstein-Barr virus-positive (EBV+), Micro Satellite Instable (MSI), genomically stable, and chromosomal unstable (CIN) forms.
#3 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. […] These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis and immune surveillance. […] Helicobacter pylori infection is the major risk factor for gastric cancer and has been considered as a Group 1 carcinogen by the International Agency for Research on Cancer. […] Recent estimates show that 89% of all non-cardia tumors (about 780,000 cases) is attributable to H. pylori infection, making this bacterium responsible for at least 6.2% of all cancer cases worldwide.
#4
https://journals.lww.com/cancerjournal/fulltext/2006/02040/pathogenesis_and_treatment_of_gastric_carcinoma_.8.aspx
Gastric cancer is one of the most common cancers and most frequent causes of cancer-related deaths in the world. The etiological factors and pathogenesis of gastric cancer are not yet fully understood. The integrated research in molecular pathology clarified the details of genetic and epigenetic abnormalities of cancer-related genes in the course of development and progression of gastric cancer. […] Epidemiological evidences indicate that environmental factors play a major role in the carcinogenesis, the role of immunological, genetic and immunogenetic factors are thought to contribute to etiopathogenesis of gastric carcinoma. […] Gastric cancer, like other cancers is the end result of the interplay of many risk factors as well as protective factors. Environmental and genetic factors are also likely to play a role in the etiology of the disease. Among the environmental factors, diet and infection with Helicobacter pylori are the most common suspects in gastric carcinogenesis. Various epidemiological and pathological studies have suggested that gastric carcinogenesis develops with the following sequential steps; chronic gastritis; atrophy; intestinal metaplasia; and dysplasia. The initial stages have been linked to excessive salt intake and infection with H. pylori. Genetic factors play an important role in gastric carcinogenesis; leading to either abnormal genes over expression or inappropriate expression of normal genes, whose products confer the malignant phenotype. Advances have been made in the genetic changes mostly of the intestinal type; its development is probably a multi-step process. The most common genetic abnormalities in gastric cancer tend to be loss of heterozygosity of tumor suppressor genes, particularly of p53 or Adenomatous Polyposis Coli gene. The latter leads to gastric oncogenesis through changes related to E-cadherin-catenin complex, which plays a critical role in the maintenance of normal tissue architecture. […] The integrated research in molecular pathology has clarified the details of genetic and epigenetic abnormalities of cancer in the course of development and progression of gastric cancer.
#5 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. […] These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis and immune surveillance. […] Helicobacter pylori infection is the major risk factor for gastric cancer and has been considered as a Group 1 carcinogen by the International Agency for Research on Cancer. […] Recent estimates show that 89% of all non-cardia tumors (about 780,000 cases) is attributable to H. pylori infection, making this bacterium responsible for at least 6.2% of all cancer cases worldwide.
#6 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. […] These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis and immune surveillance. […] Helicobacter pylori infection is the major risk factor for gastric cancer and has been considered as a Group 1 carcinogen by the International Agency for Research on Cancer. […] Recent estimates show that 89% of all non-cardia tumors (about 780,000 cases) is attributable to H. pylori infection, making this bacterium responsible for at least 6.2% of all cancer cases worldwide.
#7 Stomach Cancer – Gastrointestinal Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/gastrointestinal-disorders/tumors-of-the-gastrointestinal-tract/stomach-cancer
Etiology of stomach cancer is multifactorial, but Helicobacter pylori plays a significant role. […] Risk factors for stomach cancer include the following: Helicobacter pylori infection (when it is associated with extensive gastric intestinal metaplasia), autoimmune atrophic gastritis, smoking (and people who smoke may have an impaired response to treatment), gastric polyps, genetic factors. […] Various genetic factors are also risk factors. Hereditary diffuse gastric cancer is associated with a mutation in the cadherin 1 gene (CDH1) and has no precursor lesion. This mutation is an autosomal dominant trait with high penetrance. […] Gastric adenocarcinomas can be classified by gross appearance: Protruding: The tumor is polypoid or fungating. Penetrating: The tumor is ulcerated. Superficial spreading: The tumor spreads along the mucosa or infiltrates superficially within the wall of the stomach. Linitis plastica: The tumor infiltrates the stomach wall with an associated fibrous reaction that causes a rigid leather bottle stomach. […] Prognosis depends greatly on stage but overall is poor (5-year survival: 5 to 15%) because most patients present with advanced disease.
#8 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. […] These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis and immune surveillance. […] Helicobacter pylori infection is the major risk factor for gastric cancer and has been considered as a Group 1 carcinogen by the International Agency for Research on Cancer. […] Recent estimates show that 89% of all non-cardia tumors (about 780,000 cases) is attributable to H. pylori infection, making this bacterium responsible for at least 6.2% of all cancer cases worldwide.
#9 Stomach cancer – Wikipedia
https://en.wikipedia.org/wiki/Stomach_cancer
The bacterium Helicobacter pylori accounts for more than 60% of cases of stomach cancer. […] The mechanism by which H. pylori induces stomach cancer potentially involves chronic inflammation, the action of H. pylori virulence factors such as CagA, or an interaction between H. pylori infection and germline pathogenic variants in homologous-recombination genes. […] Bile reflux, in addition to Helicobacter pylori infection, is a pathogenic factor in gastric intestinal metaplasia, a precancerous lesion of gastric cancer. Long-term irritation of the gastric mucosa caused by bile reflux appears to have a role in gastric carcinogenesis. Bile acids, which are a significant component of bile reflux, may be a causal factor in gastric carcinogenesis.
#10 Stomach cancer – Wikipedia
https://en.wikipedia.org/wiki/Stomach_cancer
The bacterium Helicobacter pylori accounts for more than 60% of cases of stomach cancer. […] The mechanism by which H. pylori induces stomach cancer potentially involves chronic inflammation, the action of H. pylori virulence factors such as CagA, or an interaction between H. pylori infection and germline pathogenic variants in homologous-recombination genes. […] Bile reflux, in addition to Helicobacter pylori infection, is a pathogenic factor in gastric intestinal metaplasia, a precancerous lesion of gastric cancer. Long-term irritation of the gastric mucosa caused by bile reflux appears to have a role in gastric carcinogenesis. Bile acids, which are a significant component of bile reflux, may be a causal factor in gastric carcinogenesis.
#11 Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms
https://www.mdpi.com/1422-0067/24/3/2895
H. pylori infection results in a reduced ability of the infected cells to repair DNA damage. Such an effect may increase genetic instability and progressively lead to the accumulation of mutations that, in turn, can activate oncogenes and deactivate tumor suppressor genes, with the ultimate result of increasing the risk of developing gastric cancer over time. […] Chronic inflammation contributes to the pathogenesis of several types of malignant diseases and is particularly relevant for H. pylori-related gastric tumorigenesis. […] H. pylori infection leads to inflammatory reactions through a variety of molecular pathways induced in both gastric epithelial cells, which the bacterium first contacts, and in circulating immune cells recruited to the site of infection, such as neutrophils, macrophages, and lymphocytes.
#12 Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-031-47331-9_2
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. […] Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. […] Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. […] Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA.
#13 Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-031-47331-9_2
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. […] Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. […] Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. […] Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA.
#14 Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms
https://www.mdpi.com/1422-0067/24/3/2895
H. pylori infection causes inflammation and leads both directly and indirectly to DNA damage, such as oxidative damage and DSBs, in host cells. Furthermore, the resulting genetic and/or epigenetic disturbances alter the choice of DNA repair paths. These changes cause inaccurate DNA repair, genomic instability, and chromosomal aberration, which may ultimately promote gastric carcinogenesis. […] Aberrant hypermethylation of the promoter CpG islands of tumor suppressor genes, leading to their inactivation, occurs at high levels during gastric inflammation and carcinogenesis. […] Taken together, these findings indicate that various modifications of DNA repair functions are closely associated with DSB formation and chromosomal abnormalities during the development of H. pylori-related gastric cancers.
#15 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
The mechanisms of malignant transformation mediated by H. pylori infection are discussed in chapters 2, 811 and 13. […] Epstein Barr virus (EBV) is considered to be a human carcinogen linked to development of several types of lymphoma and carcinoma, accounting for about 200,000 new cancer cases annually worldwide. […] Approximately 9% of gastric cancer cases have latent EBV infection in every tumor cell. […] EBV reactivation from latency is a postulated mechanism for the development of EBV-associated malignancies. […] Taken together, much has been learned about EBV-positive gastric cancer since it was first documented, but important knowledge gaps remain. […] It is still unclear when and how the virus appears in the gastric epithelium prior to tumor emergence. […] Elucidating the viral contribution to gastric cancer pathophysiology could lead to novel strategies for prevention and treatment, with possible extension to other EBV-related malignancies.
#16 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
The mechanisms of malignant transformation mediated by H. pylori infection are discussed in chapters 2, 811 and 13. […] Epstein Barr virus (EBV) is considered to be a human carcinogen linked to development of several types of lymphoma and carcinoma, accounting for about 200,000 new cancer cases annually worldwide. […] Approximately 9% of gastric cancer cases have latent EBV infection in every tumor cell. […] EBV reactivation from latency is a postulated mechanism for the development of EBV-associated malignancies. […] Taken together, much has been learned about EBV-positive gastric cancer since it was first documented, but important knowledge gaps remain. […] It is still unclear when and how the virus appears in the gastric epithelium prior to tumor emergence. […] Elucidating the viral contribution to gastric cancer pathophysiology could lead to novel strategies for prevention and treatment, with possible extension to other EBV-related malignancies.
#17 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
The mechanisms of malignant transformation mediated by H. pylori infection are discussed in chapters 2, 811 and 13. […] Epstein Barr virus (EBV) is considered to be a human carcinogen linked to development of several types of lymphoma and carcinoma, accounting for about 200,000 new cancer cases annually worldwide. […] Approximately 9% of gastric cancer cases have latent EBV infection in every tumor cell. […] EBV reactivation from latency is a postulated mechanism for the development of EBV-associated malignancies. […] Taken together, much has been learned about EBV-positive gastric cancer since it was first documented, but important knowledge gaps remain. […] It is still unclear when and how the virus appears in the gastric epithelium prior to tumor emergence. […] Elucidating the viral contribution to gastric cancer pathophysiology could lead to novel strategies for prevention and treatment, with possible extension to other EBV-related malignancies.
#18 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. EpsteinBarr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression.
#19 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. The role of the microorganisms in gastric tumorigenesis attracts much attention in recent years. These microorganisms include bacteria, virus, and fungi. Among them, Helicobacter pylori (H. pylori) infection is by far the most important risk factor for GC development, with special reference to the early-onset cases. H. pylori targets multiple cellular components by utilizing various virulence factors to modulate the host proliferation, apoptosis, migration, and inflammatory response. EpsteinBarr virus (EBV) serves as another major risk factor in gastric carcinogenesis. The virus protein, EBER noncoding RNA, and EBV miRNAs contribute to the tumorigenesis by modulating host genome methylation and gene expression.
#20 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The infectious pathogens include viruses, bacteria, and parasites. Among the pathogens, Helicobacter pylori (H. pylori), human papillomavirus, hepatitis B virus (HBV), and hepatitis C virus together attributed to 2 million new cancer cases worldwide in 2012. They induced the tumorigenicity of the stomach, liver, and cervix. Of note, HBV and H. pylori have most vicious contributions to the tumor burden in China. H. pylori and EBV are the most well-known pathogens in gastric carcinogenesis. H. pylori is an important risk factor found in 65-80% of primary GCs, while EBV leads to 10% of the GC cases. […] World Health Organization designates H. pylori as a class I carcinogen because of its chronic infection as the strongest risk factor for gastric adenocarcinoma. It was estimated that 90% of all noncardia GCs are associated with H. pylori. A study with 1526 Japanese population found the increasing risk of GC development in patients infected with H. pylori compared with the uninfected ones. The eradication of H. pylori significantly decreased the occurrence of GC, suggesting that H. pylori might influence early stages in gastric carcinogenesis.
#21 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The potential molecular network of H. pylori and oncogenic signaling pathways in gastric carcinogenesis are summarized in Fig. 1. […] The host immune system is the formidable barrier to prevent H. pylori infection. The immune system includes innate immune response and adaptive immune response. Innate immune response is the first-line defense. Epithelial cells, dendritic cells, monocytes, macrophages, and neutrophils could play important roles in defending H. pylori infection. […] EBV is classified as a group I carcinogen by the International Agency for Research on Cancer, since the latently infection estimated to be responsible for 200,000 cancers cases worldwide, such as Burkitt lymphoma, hemophagocytic lymphohistiocytosis, Hodgkins lymphoma, GC, and nasopharyngeal carcinoma (NPC). […] The first puzzle about EBV-associated gastric carcinoma (EBVaGC) is how EBV infects gastric epithelial cells, as the EBV infection often occurs in B lymphocytes and the oral epithelium.
#22 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
It is well known that EBV LMP1 and nuclear antigen 2 (EBNA2) play major roles in EBV-induced oncogenesis. However both of them were rarely detected in gastric adenocarcinoma cells. Instead, EBNA1 expression was confirmed. […] The molecular pathogenesis of EBVaGC has not yet been comprehensively deciphered. In general, virologic aspects and genetic abnormalities of host cells co-potentiate the tumor development. As for virologic aspects, since EBV-positive GC is in latency type I, only EBERs, EBNA1, and miR-BARTs are highly expressed, while LMP2A could be detected in some cases.
#23 The JAK/STAT signaling cascade in gastric carcinoma (Review)
https://www.spandidos-publications.com/10.3892/ijo.2015.3160
Gastric carcinoma remains one of the most prevalent forms of cancer worldwide, despite the decline in incidence rates, increased awareness of the disease and advancement in treatment strategies. […] Recent studies on the genomic landscape of gastric adenocarcinoma have identified several key signaling molecules, including epidermal growth factor receptor family (ErbB) members, vascular endothelial growth factor receptor family (VEGFR) members and PI3K/Akt/mTOR pathway components, that have been implicated in the molecular pathogenesis of gastric cancers. […] The JAK/STAT cascade is a principal signal transduction pathway in cytokine and growth factor signaling, regulating various cellular processes such as cell proliferation, differentiation, migration and survival. […] Numerous in vivo and in vitro studies have shown that dysregulated JAK/STAT signaling is a driving force in the pathogenesis of various solid cancers as well as hematopoietic malignancies.
#24 The JAK/STAT signaling cascade in gastric carcinoma (Review)
https://www.spandidos-publications.com/10.3892/ijo.2015.3160
Gastric carcinoma remains one of the most prevalent forms of cancer worldwide, despite the decline in incidence rates, increased awareness of the disease and advancement in treatment strategies. […] Recent studies on the genomic landscape of gastric adenocarcinoma have identified several key signaling molecules, including epidermal growth factor receptor family (ErbB) members, vascular endothelial growth factor receptor family (VEGFR) members and PI3K/Akt/mTOR pathway components, that have been implicated in the molecular pathogenesis of gastric cancers. […] The JAK/STAT cascade is a principal signal transduction pathway in cytokine and growth factor signaling, regulating various cellular processes such as cell proliferation, differentiation, migration and survival. […] Numerous in vivo and in vitro studies have shown that dysregulated JAK/STAT signaling is a driving force in the pathogenesis of various solid cancers as well as hematopoietic malignancies.
#25 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
The development of gastric cancer is induced by H. pylori. Key aspects of bacterial pathopoiesis involve flagellar motility, mechanisms of adhesion, disruption of intercellular junctions, and damage to the gastric epithelium via vacuolization. The H. pylori virulence factors activate STAT3, NF-B, ERK, Akt, and Wnt/-catenin signaling pathways, and exert key roles in abnormal motogenic signal, hummingbird phenotype, motility and proliferation, cytoskeletal rearrangement, and disruption of cell polarity, leading to gastric carcinogenesis. […] The transcription factor STAT3 is instrumental in the gastric cancer progression stimulated by H. pylori. […] In conclusion, sustained activation of STAT3 represents a key molecular mechanism by which H. pylori promotes gastric carcinogenesis. This pathway, regulated by virulence factors such as CagA and other signalings like TLRs, triggers complicated oncogenic effects, including but not limited to cell proliferation, differentiation, inhibition of apoptosis, and EMT.
#26 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
NF-B is a key nuclear transcription factor in gastric carcinogenesis initiated by H. pylori. […] In conclusion, the NF-B pathway functions as a key effector in the development of H. pylori-mediated gastric cancer. It is not only involved in the manipulation of the immune responses but also directly drives various carcinogenic behaviors of tumor cells. […] Wnt/-catenin signaling pathway is a key regulatory mechanism in H. pylori-related gastric cancer. […] In conclusion, Wnt/-catenin signaling pathway is an important driving factor for the induction of gastric cancer by H. pylori, and this pathway plays a crucial role in various stages of carcinogenesis, including the early initiation and progression of gastric cancer. […] The chronic inflammatory response triggered by H. pylori is a significant risk factor for gastric carcinogenesis, involving complex interactions with other carcinogenic processes, such as oxidative stress and aberrant activation of cancer pathways. […] The chronic inflammatory response stimulated by H. pylori is a critical mechanism in gastric carcinogenesis. Inflammatory cells and their mediators are involved in multiple stages of gastric carcinogenesis, including DNA damage, gene mutation, and the formation of the tumor microenvironment.
#27 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis, and also reflects the genetic instability of the tumor cells like other types of genetic alterations. […] The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. […] The Wnt signaling pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC. […] NF-B is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation. […] In early stages of GC, TGF- signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis.
#28 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
NF-B is a key nuclear transcription factor in gastric carcinogenesis initiated by H. pylori. […] In conclusion, the NF-B pathway functions as a key effector in the development of H. pylori-mediated gastric cancer. It is not only involved in the manipulation of the immune responses but also directly drives various carcinogenic behaviors of tumor cells. […] Wnt/-catenin signaling pathway is a key regulatory mechanism in H. pylori-related gastric cancer. […] In conclusion, Wnt/-catenin signaling pathway is an important driving factor for the induction of gastric cancer by H. pylori, and this pathway plays a crucial role in various stages of carcinogenesis, including the early initiation and progression of gastric cancer. […] The chronic inflammatory response triggered by H. pylori is a significant risk factor for gastric carcinogenesis, involving complex interactions with other carcinogenic processes, such as oxidative stress and aberrant activation of cancer pathways. […] The chronic inflammatory response stimulated by H. pylori is a critical mechanism in gastric carcinogenesis. Inflammatory cells and their mediators are involved in multiple stages of gastric carcinogenesis, including DNA damage, gene mutation, and the formation of the tumor microenvironment.
#29 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis, and also reflects the genetic instability of the tumor cells like other types of genetic alterations. […] The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. […] The Wnt signaling pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC. […] NF-B is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation. […] In early stages of GC, TGF- signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis.
#30 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis, and also reflects the genetic instability of the tumor cells like other types of genetic alterations. […] The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. […] The Wnt signaling pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC. […] NF-B is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation. […] In early stages of GC, TGF- signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis.
#31 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#32 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis, and also reflects the genetic instability of the tumor cells like other types of genetic alterations. […] The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. […] The Wnt signaling pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC. […] NF-B is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation. […] In early stages of GC, TGF- signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis.
#33 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#34 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#35 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis, and also reflects the genetic instability of the tumor cells like other types of genetic alterations. […] The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. […] The Wnt signaling pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC. […] NF-B is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation. […] In early stages of GC, TGF- signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis.
#36 Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms
https://www.mdpi.com/1422-0067/24/3/2895
H. pylori infection causes inflammation and leads both directly and indirectly to DNA damage, such as oxidative damage and DSBs, in host cells. Furthermore, the resulting genetic and/or epigenetic disturbances alter the choice of DNA repair paths. These changes cause inaccurate DNA repair, genomic instability, and chromosomal aberration, which may ultimately promote gastric carcinogenesis. […] Aberrant hypermethylation of the promoter CpG islands of tumor suppressor genes, leading to their inactivation, occurs at high levels during gastric inflammation and carcinogenesis. […] Taken together, these findings indicate that various modifications of DNA repair functions are closely associated with DSB formation and chromosomal abnormalities during the development of H. pylori-related gastric cancers.
#37 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#38 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs). Its overexpression has been reported in various human cancers, including GC. […] Many other molecular events are also found in gastric carcinogenesis. For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN). […] In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis. […] Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.
#39 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs). Its overexpression has been reported in various human cancers, including GC. […] Many other molecular events are also found in gastric carcinogenesis. For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN). […] In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis. […] Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.
#40 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs). Its overexpression has been reported in various human cancers, including GC. […] Many other molecular events are also found in gastric carcinogenesis. For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN). […] In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis. […] Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.
#41 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
In genomically stable subtype, RHOA mutation was detected. […] The lack of cellular cohesion is a hallmark for this diffuse phenotype. […] The last group of GC was clustered as CIN subtype. […] The tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development. […] There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years.
#42 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
In genomically stable subtype, RHOA mutation was detected. […] The lack of cellular cohesion is a hallmark for this diffuse phenotype. […] The last group of GC was clustered as CIN subtype. […] The tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development. […] There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years.
#43 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
Comprehensive understanding of the detailed molecular mechanisms and accurate pathogenesis of GC will improve patient outcome. Recently, several kinds of molecular classification of GC have been provided to reveal the genomic landscape of GC and decipher the crucial molecular changes. […] The Cancer Genome Atlas (TCGA) classification is a milestone for the molecular characterization of GC. […] The most highly transcribed EBV viral, message RNAs (mRNAs) and microRNAs (miRNAs), fell within the BamH1A region of the viral genome and showed similar expression patterns across tumors. […] The mutation rate of PIK3CA is exclusively high in EBV-positive gastric cancer compared with other molecular subtypes. […] The next subtypes of GC are abundant in MSI, which display increased mutation rates (in major histocompatibility complex class I genes, including B2M and HLA-B) and hypermethylation (containing hypermethylation at the MLH1 promoter).
#44 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
In genomically stable subtype, RHOA mutation was detected. […] The lack of cellular cohesion is a hallmark for this diffuse phenotype. […] The last group of GC was clustered as CIN subtype. […] The tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development. […] There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years.
#45
https://www.alliedacademies.org/articles/short-description-of-molecular-pathogenesis-of-gastric-cancer-23296.html
Gain or loss of whole chromosomes (aneuploidy) or parts of chromosomes Loss Of Heterozygosity (LOH), and translocations are the signitures of CIN in sporadic gastric tumors. […] Mutational activation and/or amplification of oncogenes, mutations, LOH and epigenetic inactivation of tumor supressor genes, mutational inactivation and downregulation of genes encoding cell-adhesion molecules, inactivation of cell cycle regulators and aberrant expression of growth factors and cytokines play a pivotal role in the pathogenesis of gastric cancer. […] Gastric cancer due to Helicobacter pylori infection is associated with bacterial virulence, genetic polymorphism of hosts, and environmental factors. […] The dynamic balance between cell proliferation and apoptosis is critical for maintaining mucosal homeostasis. Decreased apoptosis as well as increased proliferation may favor the carcinogenic process. Prolonged survival of abnormal cells can support the accumulation of sequential genetic mutations, changes in gene expression profiles and protein structure and function, which can result in gastric tumor promotion.
#46 The Pathogenesis of Gastric Carcinoma
https://www.sgo-iasgo.com/article/the-pathogenesis-of-gastric-carcinoma
Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumours, and these epithelial tumours result from the accumulation of multiple genetic defects which leads to uncontrolled growth. The most plausible pathway for gastric carcinoma indicates that the underlying mechanisms may be different for the diffuse and intestinal types of tumour. […] The changes present can be classified as consisting of abnormalities in DNA content, the karyotype (including allele loss), oncogene and tumour suppressant gene expression (or deletion), cell cycle regulation and DNA repair genes. […] Despite the heterogeneity of multiple somatic alterations in the neoplastic lesion, the implication of a molecular classification is its exploitation to identify prognostic and predictive biomarkers and to identify targets for therapy.
#47 Gastric Cancer | CancerQuest
https://cancerquest.org/patients/cancer-type/stomach-gastric-cancer
It has been reported that TP53 is damaged (mutated) or lost in up to 80% of gastric cancers. […] However, mutations in this gene are also found in 60% of intestinal-type gastric cancers and 25% of gastric adenomas. […] Gastric cancer treatments can be divided into two categories based on the cancer: early stage and advanced stage. […] The removal of the surrounding lymph nodes is frequently done during any type of surgery. […] Many genetic changes occur in cancer. […] One of the more common mutations in hereditary gastric cancer occurs in the CDH1 gene which acts as a tumor suppressor and plays a role in cell signaling.
#48 Gastric Cancer | CancerQuest
https://cancerquest.org/patients/cancer-type/stomach-gastric-cancer
It has been reported that TP53 is damaged (mutated) or lost in up to 80% of gastric cancers. […] However, mutations in this gene are also found in 60% of intestinal-type gastric cancers and 25% of gastric adenomas. […] Gastric cancer treatments can be divided into two categories based on the cancer: early stage and advanced stage. […] The removal of the surrounding lymph nodes is frequently done during any type of surgery. […] Many genetic changes occur in cancer. […] One of the more common mutations in hereditary gastric cancer occurs in the CDH1 gene which acts as a tumor suppressor and plays a role in cell signaling.
#49 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. […] The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer: Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components: Nuclear factor-B, Wnt/-catenin, Proliferation/stem cell.
#50 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. […] The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer: Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components: Nuclear factor-B, Wnt/-catenin, Proliferation/stem cell.
#51 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. […] The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer: Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components: Nuclear factor-B, Wnt/-catenin, Proliferation/stem cell.
#52 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Gastric cancer may occur secondary to a variety of causes including H. pylori and gastric cancer have strong correlation. This is related to nitric oxide accumulation produced by inflammatory cells responding to H. pylori infection. The pathophysiology of stomach cancer depends upon the histologic subtype. K-ras mutations is found in invasive cancers and intestinal metaplasia. Inactivation of p53 in gastric epithelial cells reduce their ability to undergo apoptosis. DNA methylation of gene promoters can silence the expression of CDH1. Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. […] The pathophysiology of gastric cancer is based on various factors leading to decreased apoptosis, increased proliferation and abnormal differentiation of gastric epithelial cells. The following etiological factors contribute to the development of gastric cancer: Helicobacter pylori infection leading to activation and dysregulation of three signaling pathways, involving three major components: Nuclear factor-B, Wnt/-catenin, Proliferation/stem cell.
#53 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#54 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#55 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#56 Pathology of Gastric Cancer | Abdominal Key
https://abdominalkey.com/pathology-of-gastric-cancer/
Approximately 10 % of all gastric cancers are familial. […] Germline mutations in the E-cadherin CDH1 gene account for 30-40 % of the rare syndrome known as hereditary diffuse gastric cancer. […] The well-defined chronic inflammation-intestinal metaplasia-glandular dysplasia-cancer sequence typically precedes the development of most intestinal type gastric adenocarcinomas. […] The precursor of diffuse gastric carcinoma is thought to originate from oxyntic gland tubule neck (or globoid) dysplasia in situ signet ring cell carcinoma. […] The location of gastric adenocarcinoma may, to some extent, reflect the pathogenesis of the disease. […] Gastric cancer represents a heterogeneous group of tumors with diverse pathogenesis, morphologic features, and molecular backgrounds. […] While the basis for the initial Laurn classification was exclusively morphologic characteristics, accumulative knowledge in the epidemiology and pathogenesis of gastric carcinoma has indicated that this classification system is also valuable in defining molecular subtypes of gastric cancer.
#57 Gastric cancer: Classification, histology and application of molecular pathology – Hu – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/427/html
Gastric carcinogenesis is a multistep and multifactorial process. […] Recent advances in molecular medicine have not only shed light on the carcinogenesis of gastric cancer, but also offered novel approaches regarding prevention, diagnosis and therapeutic intervention. […] An accumulation of genetic and molecular abnormalities occurs during gastric carcinogenesis, including activation of oncogenes, overexpression of growth factors/receptors, inactivation of tumor suppression genes, DNA repair genes and cell adhesion molecules, loss of heterogeneity and point mutations of tumor suppressor genes, and silencing of tumor suppressors by CpG island methylation. […] The inactivation of the second allele of E-cadherin through mutation, methylation, and loss of heterozygosity eventually triggers the development of gastric cancer.
#58
https://www.alliedacademies.org/articles/short-description-of-molecular-pathogenesis-of-gastric-cancer-23296.html
Gastric Cancer (GC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. […] Helicobacter pylori infection, smoked and fried food, diets low in fruit and vegetables, high salt intake, geographical location, genetic factors, age, and sex are considered risk factors for the development of stomach cancer. […] Approximately, 10% of patients with gastric cancer show familial aggregation and 13% of them have germline mutations. […] In addition to histological classification of gastric cancer genome-wide analyses of DNA copy number alterations, mutations, mRNA, miRNA, and protein patterns proposes four molecularly distinct gastric cancer subtypes categorised as Epstein-Barr virus-positive (EBV+), Micro Satellite Instable (MSI), genomically stable, and chromosomal unstable (CIN) forms.
#59 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
Comprehensive understanding of the detailed molecular mechanisms and accurate pathogenesis of GC will improve patient outcome. Recently, several kinds of molecular classification of GC have been provided to reveal the genomic landscape of GC and decipher the crucial molecular changes. […] The Cancer Genome Atlas (TCGA) classification is a milestone for the molecular characterization of GC. […] The most highly transcribed EBV viral, message RNAs (mRNAs) and microRNAs (miRNAs), fell within the BamH1A region of the viral genome and showed similar expression patterns across tumors. […] The mutation rate of PIK3CA is exclusively high in EBV-positive gastric cancer compared with other molecular subtypes. […] The next subtypes of GC are abundant in MSI, which display increased mutation rates (in major histocompatibility complex class I genes, including B2M and HLA-B) and hypermethylation (containing hypermethylation at the MLH1 promoter).
#60 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs). Its overexpression has been reported in various human cancers, including GC. […] Many other molecular events are also found in gastric carcinogenesis. For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN). […] In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis. […] Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.
#61 Chronic inflammation and gastrointestinal cancer
https://www.oaepublish.com/articles/2394-4722.166994
Chronic inflammation has been identified as an important risk factor in development of the gastrointestinal (GI) tract cancers and the underlying molecular mechanisms have been studied extensively. […] Host inflammation responses in carcinogenesis are through multiple mechanisms, such as reactive oxygen and nitration species from mononuclear phagocytes and leukocytes, immune response, and pro-inflammatory cytokines. […] Nuclear factor B(NF-B) has been considered as the central mediator of the immune response. […] Furthermore, chronic inflammation creates an environment for genomic and epigenetic changes. […] Chronic inflammation creates a microenvironment locally to induce genomic instability in cells. […] Another inducible enzyme with carcinogenic properties that is active in inflamed and malignant tissues is cyclooxygenase-2 (COX-2).
#62 Chronic inflammation and gastrointestinal cancer
https://www.oaepublish.com/articles/2394-4722.166994
NF-B has often been described as the central mediator of the immune response and as being critically involved in cancer-associated inflammation and the tissue repair response. […] Thus, chronic inflammation could lead to carcinogenesis by sustaining pro-inflammatory oncogenic signaling, angiogenesis, and immune suppression. […] Gastric adenocarcinoma is the second leading cause of cancer-related death in the world. […] However, only a few percentage of infected persons do develop neoplasia. […] The chronic inflammation in IBD often results in increased re-epithelialization of cells and cell turnover in the colonic mucosa and thus, leads to increased risk of errors in DNA repair and cell cycle regulation. […] Most recently, the gut microbiota has been also implicated in initiation and promotion of CAC. […] In this review, we have discussed the links between chronic inflammation and cancer development, with special reference to GI cancers.
#63 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
NF-B is a key nuclear transcription factor in gastric carcinogenesis initiated by H. pylori. […] In conclusion, the NF-B pathway functions as a key effector in the development of H. pylori-mediated gastric cancer. It is not only involved in the manipulation of the immune responses but also directly drives various carcinogenic behaviors of tumor cells. […] Wnt/-catenin signaling pathway is a key regulatory mechanism in H. pylori-related gastric cancer. […] In conclusion, Wnt/-catenin signaling pathway is an important driving factor for the induction of gastric cancer by H. pylori, and this pathway plays a crucial role in various stages of carcinogenesis, including the early initiation and progression of gastric cancer. […] The chronic inflammatory response triggered by H. pylori is a significant risk factor for gastric carcinogenesis, involving complex interactions with other carcinogenic processes, such as oxidative stress and aberrant activation of cancer pathways. […] The chronic inflammatory response stimulated by H. pylori is a critical mechanism in gastric carcinogenesis. Inflammatory cells and their mediators are involved in multiple stages of gastric carcinogenesis, including DNA damage, gene mutation, and the formation of the tumor microenvironment.
#64 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
NF-B is a key nuclear transcription factor in gastric carcinogenesis initiated by H. pylori. […] In conclusion, the NF-B pathway functions as a key effector in the development of H. pylori-mediated gastric cancer. It is not only involved in the manipulation of the immune responses but also directly drives various carcinogenic behaviors of tumor cells. […] Wnt/-catenin signaling pathway is a key regulatory mechanism in H. pylori-related gastric cancer. […] In conclusion, Wnt/-catenin signaling pathway is an important driving factor for the induction of gastric cancer by H. pylori, and this pathway plays a crucial role in various stages of carcinogenesis, including the early initiation and progression of gastric cancer. […] The chronic inflammatory response triggered by H. pylori is a significant risk factor for gastric carcinogenesis, involving complex interactions with other carcinogenic processes, such as oxidative stress and aberrant activation of cancer pathways. […] The chronic inflammatory response stimulated by H. pylori is a critical mechanism in gastric carcinogenesis. Inflammatory cells and their mediators are involved in multiple stages of gastric carcinogenesis, including DNA damage, gene mutation, and the formation of the tumor microenvironment.
#65 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The causal relationship between inflammation and cancer has been well recognized. An individual infected with H. pylori has a bigger chance to develop chronic inflammation. H. pylori utilizes virulence factors CagA, VacA, and peptidoglycan to upregulate proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, and NF-B, to activate NF-B signaling cascade in gastric epithelial cells and circulating immune cells. The production of cytokine triggers activation and migration of leukocytes, and regulation cascade of cytokines, chemokine, and adhesions. […] The aberrant host genetic changes are also crucial for the interaction of H. pylori and gastric epithelium cells. Polymorphisms in IL-1 and its endogenous receptor antagonist affect gastric mucosal IL-1 production in response to infection of H. pylori and are associated with GC occurrence.
#66 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The causal relationship between inflammation and cancer has been well recognized. An individual infected with H. pylori has a bigger chance to develop chronic inflammation. H. pylori utilizes virulence factors CagA, VacA, and peptidoglycan to upregulate proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, and NF-B, to activate NF-B signaling cascade in gastric epithelial cells and circulating immune cells. The production of cytokine triggers activation and migration of leukocytes, and regulation cascade of cytokines, chemokine, and adhesions. […] The aberrant host genetic changes are also crucial for the interaction of H. pylori and gastric epithelium cells. Polymorphisms in IL-1 and its endogenous receptor antagonist affect gastric mucosal IL-1 production in response to infection of H. pylori and are associated with GC occurrence.
#67 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The causal relationship between inflammation and cancer has been well recognized. An individual infected with H. pylori has a bigger chance to develop chronic inflammation. H. pylori utilizes virulence factors CagA, VacA, and peptidoglycan to upregulate proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, and NF-B, to activate NF-B signaling cascade in gastric epithelial cells and circulating immune cells. The production of cytokine triggers activation and migration of leukocytes, and regulation cascade of cytokines, chemokine, and adhesions. […] The aberrant host genetic changes are also crucial for the interaction of H. pylori and gastric epithelium cells. Polymorphisms in IL-1 and its endogenous receptor antagonist affect gastric mucosal IL-1 production in response to infection of H. pylori and are associated with GC occurrence.
#68 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The causal relationship between inflammation and cancer has been well recognized. An individual infected with H. pylori has a bigger chance to develop chronic inflammation. H. pylori utilizes virulence factors CagA, VacA, and peptidoglycan to upregulate proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, and NF-B, to activate NF-B signaling cascade in gastric epithelial cells and circulating immune cells. The production of cytokine triggers activation and migration of leukocytes, and regulation cascade of cytokines, chemokine, and adhesions. […] The aberrant host genetic changes are also crucial for the interaction of H. pylori and gastric epithelium cells. Polymorphisms in IL-1 and its endogenous receptor antagonist affect gastric mucosal IL-1 production in response to infection of H. pylori and are associated with GC occurrence.
#69 Gastric cancer: genome damaged by bugs | Oncogene
https://www.nature.com/articles/s41388-020-1241-4
The causal relationship between inflammation and cancer has been well recognized. An individual infected with H. pylori has a bigger chance to develop chronic inflammation. H. pylori utilizes virulence factors CagA, VacA, and peptidoglycan to upregulate proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-, and NF-B, to activate NF-B signaling cascade in gastric epithelial cells and circulating immune cells. The production of cytokine triggers activation and migration of leukocytes, and regulation cascade of cytokines, chemokine, and adhesions. […] The aberrant host genetic changes are also crucial for the interaction of H. pylori and gastric epithelium cells. Polymorphisms in IL-1 and its endogenous receptor antagonist affect gastric mucosal IL-1 production in response to infection of H. pylori and are associated with GC occurrence.
#70 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
Deregulation of cell apoptosis is a key event in H. pylori-induced gastric carcinogenesis, and H. pylori is capable of manipulating apoptosis in gastric epithelial cells to favor tumor survival and expansion. […] The inhibition of apoptosis is a critical molecular mechanism in carcinogenesis. H. pylori’s chronic infection and the resulting inflammatory state create a conducive environment for tumorigenesis. […] H. pylori employs additional strategies contributing to gastric cancer development, including interference with cell cycle progression and autophagy. […] The molecular mechanisms underlying H. pylori-promoted carcinogenesis are exceptionally intricate, involving the interplay of numerous pathways and interconnected links.
#71 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
Deregulation of cell apoptosis is a key event in H. pylori-induced gastric carcinogenesis, and H. pylori is capable of manipulating apoptosis in gastric epithelial cells to favor tumor survival and expansion. […] The inhibition of apoptosis is a critical molecular mechanism in carcinogenesis. H. pylori’s chronic infection and the resulting inflammatory state create a conducive environment for tumorigenesis. […] H. pylori employs additional strategies contributing to gastric cancer development, including interference with cell cycle progression and autophagy. […] The molecular mechanisms underlying H. pylori-promoted carcinogenesis are exceptionally intricate, involving the interplay of numerous pathways and interconnected links.
#72 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
Deregulation of cell apoptosis is a key event in H. pylori-induced gastric carcinogenesis, and H. pylori is capable of manipulating apoptosis in gastric epithelial cells to favor tumor survival and expansion. […] The inhibition of apoptosis is a critical molecular mechanism in carcinogenesis. H. pylori’s chronic infection and the resulting inflammatory state create a conducive environment for tumorigenesis. […] H. pylori employs additional strategies contributing to gastric cancer development, including interference with cell cycle progression and autophagy. […] The molecular mechanisms underlying H. pylori-promoted carcinogenesis are exceptionally intricate, involving the interplay of numerous pathways and interconnected links.
#73 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
Deregulation of cell apoptosis is a key event in H. pylori-induced gastric carcinogenesis, and H. pylori is capable of manipulating apoptosis in gastric epithelial cells to favor tumor survival and expansion. […] The inhibition of apoptosis is a critical molecular mechanism in carcinogenesis. H. pylori’s chronic infection and the resulting inflammatory state create a conducive environment for tumorigenesis. […] H. pylori employs additional strategies contributing to gastric cancer development, including interference with cell cycle progression and autophagy. […] The molecular mechanisms underlying H. pylori-promoted carcinogenesis are exceptionally intricate, involving the interplay of numerous pathways and interconnected links.
#74
https://www.alliedacademies.org/articles/short-description-of-molecular-pathogenesis-of-gastric-cancer-23296.html
Gain or loss of whole chromosomes (aneuploidy) or parts of chromosomes Loss Of Heterozygosity (LOH), and translocations are the signitures of CIN in sporadic gastric tumors. […] Mutational activation and/or amplification of oncogenes, mutations, LOH and epigenetic inactivation of tumor supressor genes, mutational inactivation and downregulation of genes encoding cell-adhesion molecules, inactivation of cell cycle regulators and aberrant expression of growth factors and cytokines play a pivotal role in the pathogenesis of gastric cancer. […] Gastric cancer due to Helicobacter pylori infection is associated with bacterial virulence, genetic polymorphism of hosts, and environmental factors. […] The dynamic balance between cell proliferation and apoptosis is critical for maintaining mucosal homeostasis. Decreased apoptosis as well as increased proliferation may favor the carcinogenic process. Prolonged survival of abnormal cells can support the accumulation of sequential genetic mutations, changes in gene expression profiles and protein structure and function, which can result in gastric tumor promotion.
#75 Stomach microbiota in gastric cancer development and clinical implications | Gut
https://gut.bmj.com/content/73/12/2062
Diagnosis and prognosis of GC can be assisted by signatures developed with oral, gastric mucosal and intestinal microbiota, while their efficacy needs to be improved. […] With advancements in techniques and further delving into the effects and mechanisms of gastric microbe-host interactions, the future is bright for modulating microbes in GC prevention and therapeutics in clinical practice. […] Helicobacter pylori mainly serves as the trigger for the initiation of gastric carcinogenesis, while non-H. pylori microbiota can potentially exert their impacts throughout the pathogenesis of gastric cancer through various mechanisms. […] To date, several studies have provided mechanistic insights into the links between pathobionts and GC. […] The enrichment of S. anginosus is consistently observed in mucosa biopsies of patients with GC from multiple studies. Mechanistically, our previous study demonstrated that S. anginosus produces proinflammatory cytokines, including Ccl20 and Ccl8, to induce acute inflammation in the stomach.
#76 Another common bacteria implicated in stomach cancer
https://newatlas.com/medical/common-bacteria-stomach-cancer/
A common, usually harmless bacteria have a significant role in causing stomach cancer, a new study has found. […] The H. pylori bacterium is already a known major risk factor for stomach cancer. […] Researchers identified the bacterias mechanism of action, opening the door to developing therapeutics to reduce the risk. […] The low percentage of people who develop gastric cancer because of H. pylori infection has led scientists to question whether theres an additional pathogen contributing to the disease. […] The researchers examined the mechanism underlying this process and found that S. anginosus used its surface protein, TMPC, to communicate with the Annexin A2 (ANXA2) receptor on cells in the stomach lining. The interaction allowed the bacteria to attach to and colonize the cell, activating mitogen-activated protein kinase (MAPK), an enzyme that coordinates cell proliferation, differentiation, and survival. […] We have established the role of S. anginosus in gastric carcinogenesis and its related mechanism; next, we will explore the therapeutic potential of targeting it to reduce gastric inflammation and cancer risk.
#77 Stomach microbiota in gastric cancer development and clinical implications | Gut
https://gut.bmj.com/content/73/12/2062
Collectively, while current studies focus heavily on microbial alterations and function in GC, how microbial metabolism and their metabolic products (ie, metabolites) affect gastric carcinogenesis are mostly unclear. […] Fungal dysbiosis in GC is characterised by an increased abundance of Cutaneotrichosporon, Malassezia, Solicoccozyma and Archaeorhizomyces, in two independent Chinese cohorts. […] EBV infection accounts for around 79% of global GC cases each year, and can induce significant genomic and epigenomic change to promote carcinogenesis. […] The vast majority of studies have revealed the association of gastric microbiota with the development of GC and its therapeutics. Accumulated evidence has implied that it is now the proper time to reconsider the pathogenesis and progression of GC by taking gastric microbes beyond H. pylori into account.
#78 Pulsenotes | Gastric cancer notes
https://app.pulsenotes.com/medicine/gastroenterology/notes/gastric-cancer
The Correa cascade describes the classic sequence of histological lesions for the most common gastric cancer: intestinal type adenocarcinoma. It was first described in 1975, but later linked with infection by H. pylori following its identification as a cause of gastritis in 1983. […] The sequence progresses from normal gastric mucosa to gastric dysplasia, which is high-risk of developing invasive carcinoma.
#79 Pulsenotes | Gastric cancer notes
https://app.pulsenotes.com/medicine/gastroenterology/notes/gastric-cancer
The Correa cascade describes the classic sequence of histological lesions for the most common gastric cancer: intestinal type adenocarcinoma. It was first described in 1975, but later linked with infection by H. pylori following its identification as a cause of gastritis in 1983. […] The sequence progresses from normal gastric mucosa to gastric dysplasia, which is high-risk of developing invasive carcinoma.
#80 Stomach (Gastric) Cancer Prevention (PDQÂ®) – NCI
https://www.cancer.gov/types/stomach/hp/stomach-prevention-pdq
Understanding of the pathogenesis of gastric cancer has advanced over the years. A lengthy precancerous process has been identified in which the gastric mucosa is slowly transformed from normal to chronic gastritis, to multifocal atrophy, to intestinal metaplasia of various degrees, to dysplasia, and then to invasive carcinoma. The process is apparently driven by forces acting on the gastric epithelium for many years, such as excessive dietary salt and, most prominently, infection with Helicobacter pylori. […] There is consistent evidence that Helicobacter pylori infection, also known as H. pylori infection, of the stomach is strongly associated with both the initiation and promotion of carcinoma of the gastric body and antrum and of gastric lymphoma. The International Agency for Research on Cancer classifies H. pylori infection as a cause of noncardia gastric carcinoma and gastric, low-grade, B-cell mucosa-associated lymphoid tissue or mucosa-associated lymphatic tissue (MALT) lymphoma (i.e., a Group 1 human carcinogen). […] Helicobacter pylori infection is an accepted cause of gastric adenocarcinoma.
#81 Stomach (Gastric) Cancer Prevention (PDQÂ®) – NCI
https://www.cancer.gov/types/stomach/hp/stomach-prevention-pdq
Understanding of the pathogenesis of gastric cancer has advanced over the years. A lengthy precancerous process has been identified in which the gastric mucosa is slowly transformed from normal to chronic gastritis, to multifocal atrophy, to intestinal metaplasia of various degrees, to dysplasia, and then to invasive carcinoma. The process is apparently driven by forces acting on the gastric epithelium for many years, such as excessive dietary salt and, most prominently, infection with Helicobacter pylori. […] There is consistent evidence that Helicobacter pylori infection, also known as H. pylori infection, of the stomach is strongly associated with both the initiation and promotion of carcinoma of the gastric body and antrum and of gastric lymphoma. The International Agency for Research on Cancer classifies H. pylori infection as a cause of noncardia gastric carcinoma and gastric, low-grade, B-cell mucosa-associated lymphoid tissue or mucosa-associated lymphatic tissue (MALT) lymphoma (i.e., a Group 1 human carcinogen). […] Helicobacter pylori infection is an accepted cause of gastric adenocarcinoma.
#82 Etiopathogenesis and staging of gastric cancer | PPT
https://www.slideshare.net/slideshow/etiopathogenesis-and-staging-of-gastric-cancer/246553647
7. The Cancer Genome Atlas (TCGA) project points to a new four molecular classification of gastric cancers: (i) Mesenchymal cell type – Gastric cancers positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1 and PD-L2; worst prognosis, early age, highest recurrence frequency diffuse type. […] […] 8. Gastric cancers with chromosomal instability (TP53 INACTIVE), which show marked aneuploidy and focal amplification of receptor tyrosine kinases; frequent HER2 GENE amplification- her2 targeted agents work best. […] […] 9. The most common nodal station metastases for the upper, middle, and lower third of the stomach were stations 3(lesser curvature), 3/4/7 (lesser/greater curvature/left gastric artery), and 3/4/6 (lesser/ greater curvature / infrapyloric), respectively. […]
#83 Etiopathogenesis and staging of gastric cancer | PPT
https://www.slideshare.net/slideshow/etiopathogenesis-and-staging-of-gastric-cancer/246553647
7. The Cancer Genome Atlas (TCGA) project points to a new four molecular classification of gastric cancers: (i) Mesenchymal cell type – Gastric cancers positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, PD-L1 and PD-L2; worst prognosis, early age, highest recurrence frequency diffuse type. […] […] 8. Gastric cancers with chromosomal instability (TP53 INACTIVE), which show marked aneuploidy and focal amplification of receptor tyrosine kinases; frequent HER2 GENE amplification- her2 targeted agents work best. […] […] 9. The most common nodal station metastases for the upper, middle, and lower third of the stomach were stations 3(lesser curvature), 3/4/7 (lesser/greater curvature/left gastric artery), and 3/4/6 (lesser/ greater curvature / infrapyloric), respectively. […]
#84 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#85 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#86 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#87 Stomach cancer – WikiLectures
https://www.wikilectures.eu/w/Stomach_cancer
Gastric cancer develops through a complex multistage process with several distinct histological and pathophysiological phases. […] Many of the etiologies and pathogenesis of this disease remain unclear, but the underlying context is already known. […] The diffusion type is usually associated with an unfavorable prognosis, as it often shows a strong tendency to invade the surrounding tissue. Tumor cells of this type lose cohesion and original function. Compared to the intestinal type, its pathogenesis is much less studied. […] The intestinal type has well-defined stages of development and tumor cells form into functional glands of the gastrointestinal tract.
#88 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#89 Stomach cancer pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Stomach_cancer_pathophysiology
Beta-catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Beta-catenin is a part of Wnt signaling pathway which regulates coordination of events such as intercellular adhesion junctions, migration, proliferation, and differentiation. APC gene protein prevents the accumulation of beta-catenin. APC mutations lead to loss of regulation of beta-catenin which leads to proliferation, angiogenesis, tumor invasion, and metastasis of cells. […] Diffuse gastric carcinomas do not have a precancerous lesion. They are highly metastatic with a poorer prognosis than intestinal cancers. When the entire stomach wall is infiltrated, it results in a rigid thickened stomach wall called linitis plastica. Somatic mutations in the CDH1 gene by hypermethylation, mutation, and loss of heterozygosity are identified in 40 to 83 percent of sporadic diffuse-type gastric cancers.
#90 Carcinoma Stomach: INTESTINAL VS DIFFUSE GASTRIC CANCER – Pathology Made Simple
https://ilovepathology.com/carcinoma-stomach-intestinal-vs-diffuse-gastric-cancer/
The key mechanism in diffuse type gastric cancer is the loss of a protein called E-cadherin. E-cadherin is responsible for cell adhesion, helping cells attach to one another. Loss of E-cadherin results in the dissociation of cells. This loss can occur due to mutations in the tumor suppressor gene called cdh1, which encodes E-cadherin. Additionally, hypermethylation and silencing of the cdh1 promoter region can also lead to the loss of E-cadherin. The loss of E-cadherin in diffuse type gastric cancer causes the infiltration of tumor cells throughout the gastric wall. This infiltration evokes a desmoplastic response, leading to stiffening of the stomach wall. The affected areas show diffuse rugal flattening and a rigid, thickened appearance resembling a leather bottle (linitis plastica) on imaging. Its important to note that diffuse type gastric cancer usually occurs sporadically, while intestinal type gastric cancer can be associated with H. pylori infection and specific dietary factors. Familial cases of gastric cancer are more commonly of the diffuse type.
#91 Carcinoma Stomach: INTESTINAL VS DIFFUSE GASTRIC CANCER – Pathology Made Simple
https://ilovepathology.com/carcinoma-stomach-intestinal-vs-diffuse-gastric-cancer/
The key mechanism in diffuse type gastric cancer is the loss of a protein called E-cadherin. E-cadherin is responsible for cell adhesion, helping cells attach to one another. Loss of E-cadherin results in the dissociation of cells. This loss can occur due to mutations in the tumor suppressor gene called cdh1, which encodes E-cadherin. Additionally, hypermethylation and silencing of the cdh1 promoter region can also lead to the loss of E-cadherin. The loss of E-cadherin in diffuse type gastric cancer causes the infiltration of tumor cells throughout the gastric wall. This infiltration evokes a desmoplastic response, leading to stiffening of the stomach wall. The affected areas show diffuse rugal flattening and a rigid, thickened appearance resembling a leather bottle (linitis plastica) on imaging. Its important to note that diffuse type gastric cancer usually occurs sporadically, while intestinal type gastric cancer can be associated with H. pylori infection and specific dietary factors. Familial cases of gastric cancer are more commonly of the diffuse type.
#92 Carcinoma Stomach: INTESTINAL VS DIFFUSE GASTRIC CANCER – Pathology Made Simple
https://ilovepathology.com/carcinoma-stomach-intestinal-vs-diffuse-gastric-cancer/
The key mechanism in diffuse type gastric cancer is the loss of a protein called E-cadherin. E-cadherin is responsible for cell adhesion, helping cells attach to one another. Loss of E-cadherin results in the dissociation of cells. This loss can occur due to mutations in the tumor suppressor gene called cdh1, which encodes E-cadherin. Additionally, hypermethylation and silencing of the cdh1 promoter region can also lead to the loss of E-cadherin. The loss of E-cadherin in diffuse type gastric cancer causes the infiltration of tumor cells throughout the gastric wall. This infiltration evokes a desmoplastic response, leading to stiffening of the stomach wall. The affected areas show diffuse rugal flattening and a rigid, thickened appearance resembling a leather bottle (linitis plastica) on imaging. Its important to note that diffuse type gastric cancer usually occurs sporadically, while intestinal type gastric cancer can be associated with H. pylori infection and specific dietary factors. Familial cases of gastric cancer are more commonly of the diffuse type.
#93 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#94 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#95 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#96 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#97 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#98 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. […] An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. […] The etiology of DGC is diverse. […] In addition to environmental etiologies, somatic and germline mutations in a number of genes can contribute to the development of DGC. […] Approximately 13% of all GCs are due to hereditary diffuse gastric cancer (HDGC), with 40% of those associated with germline mutations in CDH1. […] The most common CDH1 mutations seen are truncating mutations or predicted to be deleterious missense mutations in the cadherin domain, occurring 2.5 times more frequently in those with signet ring cell phenotype and predicted to be associated with loss of function.
#99 Diffuse gastric cancer: histologic, molecular, and genetic basis of disease – Iyer – Translational Gastroenterology and Hepatology
https://tgh.amegroups.org/article/view/5746/html
In all cases, CDH1 mutations were clonal and co-occurred with mutations in TP53, another important tumor suppressor gene, suggesting that this mutation is acquired early in the pathogenesis of the disease. […] RHOA is a gene that encodes a small GTPase, and is involved in cell migration via actin organization, cytokinesis, and the cell cycle; it is somatically mutated in up to 25.3% of DG cases. […] In addition to somatic mutations in CDH1 and RHOA, a study of WES on 23 DGC samples identified mutations in CMTM2, a member of a chemokine-like factor superfamily, as a driver mutation in DGC with lymph node metastases. […] The study also found a difference in mutational patterns between N0 and N3 tumors, suggesting both molecular and clinical heterogeneity within DGC. […] CLDN18-ARHGAP fusions have been noted in ~15% of DGC and may be associated with larger tumors, greater rate of lymph node metastases, and more advanced disease presentation compared to fusion-negative DGC patients.
#100 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
In genomically stable subtype, RHOA mutation was detected. […] The lack of cellular cohesion is a hallmark for this diffuse phenotype. […] The last group of GC was clustered as CIN subtype. […] The tumor microenvironment composed of multiple subjects, such as tumor stromal fibroblasts, lymphocytes, and angiogenic factors. All these components cooperate together, configuring a context for GC development. […] There is still a large realm of the unknown area about GC pathogenies even though the related research studies have been going deeper and our horizon has been broadened in the past few years.
#101 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
The TME of GC has great plasticity and undergoes continuous alterations and stage-specific modifications in response to various cancer cell-intrinsic and -extrinsic factors. Networks of cytokines and growth factors disrupt signaling pathways, and modified molecular signatures in the stroma characterize these changes in the TME. Previous efforts to characterize TME have underscored the pivotal role of the interaction between tumor cells and stroma in driving GC carcinogenesis, progression, and metastasis. […] CAFs are a main resource of the stroma and secrete soluble factors such as chemokines, cytokines, and growth factors to employ distinct cell types to the TME and reprogram them. CAFs also produce inflammatory ligands and ECM proteins, which in turn promote tumor growth, invasion, and migration of cancer cells, as well as immune evasion and resistance to anti-cancer therapies.
#102 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
The TME of GC has great plasticity and undergoes continuous alterations and stage-specific modifications in response to various cancer cell-intrinsic and -extrinsic factors. Networks of cytokines and growth factors disrupt signaling pathways, and modified molecular signatures in the stroma characterize these changes in the TME. Previous efforts to characterize TME have underscored the pivotal role of the interaction between tumor cells and stroma in driving GC carcinogenesis, progression, and metastasis. […] CAFs are a main resource of the stroma and secrete soluble factors such as chemokines, cytokines, and growth factors to employ distinct cell types to the TME and reprogram them. CAFs also produce inflammatory ligands and ECM proteins, which in turn promote tumor growth, invasion, and migration of cancer cells, as well as immune evasion and resistance to anti-cancer therapies.
#103 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
During tumor progression, CAFs promote the secretion of key structural proteins, including collagen type I-V and elastin, which participate in basement membrane (BM) formation, inflammation, and angiogenesis. […] It has been observed that the lysyl oxidase-like 2 (LOXL2) enzyme, which catalyzes the crosslinking of ECM to construct stable collagen I, was increasingly secreted by gastric CAFs compared with normal gastric fibroblasts. LOX2 activated the FAK/Src pathway, leading to enhanced migration and invasion of GC cells. […] The activation of TGFBR3-regulated TGF-Î² signaling was prompted by an extracellular sulfatase, human sulfatase 1, secreted by CAFs. This interaction also causes the promotion of EMT, resistance to chemotherapy in GC cells, and metastasis mediated by TGF-Î² signaling.
#104 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
During tumor progression, CAFs promote the secretion of key structural proteins, including collagen type I-V and elastin, which participate in basement membrane (BM) formation, inflammation, and angiogenesis. […] It has been observed that the lysyl oxidase-like 2 (LOXL2) enzyme, which catalyzes the crosslinking of ECM to construct stable collagen I, was increasingly secreted by gastric CAFs compared with normal gastric fibroblasts. LOX2 activated the FAK/Src pathway, leading to enhanced migration and invasion of GC cells. […] The activation of TGFBR3-regulated TGF-Î² signaling was prompted by an extracellular sulfatase, human sulfatase 1, secreted by CAFs. This interaction also causes the promotion of EMT, resistance to chemotherapy in GC cells, and metastasis mediated by TGF-Î² signaling.
#105 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
During tumor progression, CAFs promote the secretion of key structural proteins, including collagen type I-V and elastin, which participate in basement membrane (BM) formation, inflammation, and angiogenesis. […] It has been observed that the lysyl oxidase-like 2 (LOXL2) enzyme, which catalyzes the crosslinking of ECM to construct stable collagen I, was increasingly secreted by gastric CAFs compared with normal gastric fibroblasts. LOX2 activated the FAK/Src pathway, leading to enhanced migration and invasion of GC cells. […] The activation of TGFBR3-regulated TGF-Î² signaling was prompted by an extracellular sulfatase, human sulfatase 1, secreted by CAFs. This interaction also causes the promotion of EMT, resistance to chemotherapy in GC cells, and metastasis mediated by TGF-Î² signaling.
#106 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. […] Recently, metabolic parameters of tumor tissues, such as extracellular acidity have been proposed to be critical in tumor malignancy and resistance to therapeutic agents. […] Such acidosis has been reported to confer an ineffective therapeutic environment leading to selection of more resistant and aggressive characteristics. […] However, the mechanisms by which acidic pH microenvironment induces resistance in cancer cells are not well understood. […] Therefore, we questioned whether extracellular acidity can also affect the upstream lipid-mediated signaling that is linked to COX pathway. […] Acidic culture conditions increased PLA2 activity in GC cells.
#107 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. […] Recently, metabolic parameters of tumor tissues, such as extracellular acidity have been proposed to be critical in tumor malignancy and resistance to therapeutic agents. […] Such acidosis has been reported to confer an ineffective therapeutic environment leading to selection of more resistant and aggressive characteristics. […] However, the mechanisms by which acidic pH microenvironment induces resistance in cancer cells are not well understood. […] Therefore, we questioned whether extracellular acidity can also affect the upstream lipid-mediated signaling that is linked to COX pathway. […] Acidic culture conditions increased PLA2 activity in GC cells.
#108 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. […] Recently, metabolic parameters of tumor tissues, such as extracellular acidity have been proposed to be critical in tumor malignancy and resistance to therapeutic agents. […] Such acidosis has been reported to confer an ineffective therapeutic environment leading to selection of more resistant and aggressive characteristics. […] However, the mechanisms by which acidic pH microenvironment induces resistance in cancer cells are not well understood. […] Therefore, we questioned whether extracellular acidity can also affect the upstream lipid-mediated signaling that is linked to COX pathway. […] Acidic culture conditions increased PLA2 activity in GC cells.
#109 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. […] Recently, metabolic parameters of tumor tissues, such as extracellular acidity have been proposed to be critical in tumor malignancy and resistance to therapeutic agents. […] Such acidosis has been reported to confer an ineffective therapeutic environment leading to selection of more resistant and aggressive characteristics. […] However, the mechanisms by which acidic pH microenvironment induces resistance in cancer cells are not well understood. […] Therefore, we questioned whether extracellular acidity can also affect the upstream lipid-mediated signaling that is linked to COX pathway. […] Acidic culture conditions increased PLA2 activity in GC cells.
#110 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Extracellular acidity, a characteristic of solid tumors, has been proposed to be a critical factor for aggravating tumor malignancy and conferring resistance to therapeutics. […] Recently, metabolic parameters of tumor tissues, such as extracellular acidity have been proposed to be critical in tumor malignancy and resistance to therapeutic agents. […] Such acidosis has been reported to confer an ineffective therapeutic environment leading to selection of more resistant and aggressive characteristics. […] However, the mechanisms by which acidic pH microenvironment induces resistance in cancer cells are not well understood. […] Therefore, we questioned whether extracellular acidity can also affect the upstream lipid-mediated signaling that is linked to COX pathway. […] Acidic culture conditions increased PLA2 activity in GC cells.
#111 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#112 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#113 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#114 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#115 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#116 Extracellular Acidity-mediated Expression of cPLA2Î³ Confers Resistance in Gastric Cancer Cells | Anticancer Research
https://ar.iiarjournals.org/content/41/1/211
Therefore, PLA2 enzymes appear to be activated or up-regulated under acidic pH conditions in these cells. […] Since acidic pH conditions increased the PLA2 activity in GC cells, we explored whether the acidity influences the expression of cellular PLA2 enzymes. […] This result indicates that acidic pH conditions increase the expression of cPLA2 in both SNU601 and AGS GC cells. […] Therefore, an increased expression of cPLA2 may play a role in protecting SNU601 cells from the cytotoxic effect triggered by the acidic environment. […] Thus, an increase in cPLA2 expression appears to be involved in acidity-mediated resistance to anticancer drugs by reducing apoptosis of tumor cells. […] Conclusively, based on the findings of the present study, we suggest that cPLA2 could be an important therapeutic target for resistant cancer cells under acidic environment.
#117 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Gastric cancer is one of the most malignant tumors worldwide and remains a major health threat in Asia-Pacific regions, while its pathological mechanism is generally unknown. […] In the past decades, studies aimed at Helicobacter pylori infection, hereditary susceptibility and environmental factors have made a great breakthrough in investigating its precise pathogenesis. […] Recently, application of various ’-omics’ technologies opened a new field to investigate the mechanisms behind this disease. […] With the emergency of metabolomics, major progress has been made in the understanding of the relationship between metabolic regulation and cancer. […] Extensive research also indicates that metabolic reprogramming is one of the hallmarks of cancer, and intricately linked to oncogenesis and cancer immune escape.
#118 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Gastric cancer is one of the most malignant tumors worldwide and remains a major health threat in Asia-Pacific regions, while its pathological mechanism is generally unknown. […] In the past decades, studies aimed at Helicobacter pylori infection, hereditary susceptibility and environmental factors have made a great breakthrough in investigating its precise pathogenesis. […] Recently, application of various ’-omics’ technologies opened a new field to investigate the mechanisms behind this disease. […] With the emergency of metabolomics, major progress has been made in the understanding of the relationship between metabolic regulation and cancer. […] Extensive research also indicates that metabolic reprogramming is one of the hallmarks of cancer, and intricately linked to oncogenesis and cancer immune escape.
#119 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Gastric cancer is one of the most malignant tumors worldwide and remains a major health threat in Asia-Pacific regions, while its pathological mechanism is generally unknown. […] In the past decades, studies aimed at Helicobacter pylori infection, hereditary susceptibility and environmental factors have made a great breakthrough in investigating its precise pathogenesis. […] Recently, application of various ’-omics’ technologies opened a new field to investigate the mechanisms behind this disease. […] With the emergency of metabolomics, major progress has been made in the understanding of the relationship between metabolic regulation and cancer. […] Extensive research also indicates that metabolic reprogramming is one of the hallmarks of cancer, and intricately linked to oncogenesis and cancer immune escape.
#120 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Gastric cancer is one of the most malignant tumors worldwide and remains a major health threat in Asia-Pacific regions, while its pathological mechanism is generally unknown. […] In the past decades, studies aimed at Helicobacter pylori infection, hereditary susceptibility and environmental factors have made a great breakthrough in investigating its precise pathogenesis. […] Recently, application of various ’-omics’ technologies opened a new field to investigate the mechanisms behind this disease. […] With the emergency of metabolomics, major progress has been made in the understanding of the relationship between metabolic regulation and cancer. […] Extensive research also indicates that metabolic reprogramming is one of the hallmarks of cancer, and intricately linked to oncogenesis and cancer immune escape.
#121 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Gastric cancer is one of the most malignant tumors worldwide and remains a major health threat in Asia-Pacific regions, while its pathological mechanism is generally unknown. […] In the past decades, studies aimed at Helicobacter pylori infection, hereditary susceptibility and environmental factors have made a great breakthrough in investigating its precise pathogenesis. […] Recently, application of various ’-omics’ technologies opened a new field to investigate the mechanisms behind this disease. […] With the emergency of metabolomics, major progress has been made in the understanding of the relationship between metabolic regulation and cancer. […] Extensive research also indicates that metabolic reprogramming is one of the hallmarks of cancer, and intricately linked to oncogenesis and cancer immune escape.
#122 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#123 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#124 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#125 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#126 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#127 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Reprogramming of glutamine metabolism further contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. […] The notable feature of lipid metabolism in cancer cells is an increased rate of lipogenesis and the upregulation of mitochondrial fatty acid -oxidation, gastric cancer shows a similar tendency and presents typical changes regarding various metabolites involving in lipid metabolism. […] Tumor cells are in a state of such rapid proliferation and differentiation that frequent nucleotide synthesis and metabolism are upregulated significantly. […] Accumulation of the end products of nucleotide catabolism is characterized by the higher levels of uric acid or urate in gastric cancer patients or animal models. […] Based on metabolomics, Wu and colleagues showed that five metabolites (increased L-cysteine, hypoxanthine and L-tyrosine; decreased phenanthrenol and butanoic acid) were detected differently between non-invasive and invasive groups. […] It is possible that changes in proline might be essential in tumor metastasis.
#128 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Reprogramming of glutamine metabolism further contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. […] The notable feature of lipid metabolism in cancer cells is an increased rate of lipogenesis and the upregulation of mitochondrial fatty acid -oxidation, gastric cancer shows a similar tendency and presents typical changes regarding various metabolites involving in lipid metabolism. […] Tumor cells are in a state of such rapid proliferation and differentiation that frequent nucleotide synthesis and metabolism are upregulated significantly. […] Accumulation of the end products of nucleotide catabolism is characterized by the higher levels of uric acid or urate in gastric cancer patients or animal models. […] Based on metabolomics, Wu and colleagues showed that five metabolites (increased L-cysteine, hypoxanthine and L-tyrosine; decreased phenanthrenol and butanoic acid) were detected differently between non-invasive and invasive groups. […] It is possible that changes in proline might be essential in tumor metastasis.
#129 Etiopathogenesis and staging of gastric cancer | PPT
https://www.slideshare.net/slideshow/etiopathogenesis-and-staging-of-gastric-cancer/246553647
5. In terms of pathogenesis, two new concepts are worth mentioning: bone marrow participation in gastric carcinogenesis and gastric cancer stem cells. It has been hypothesized that the gastric epithelial cells acquiring abnormal phenotype (resembling intestinal epithelium) originate from gastric stem cells localized to the only cell replication zone of the gastric glands (i.e., the isthmus). […] […] 6. Although controversial, cancer stem cells are defined as cancer cells with the exclusive ability to initiate tumors, metastasize, and self-renew tumors. In gastric cancer, several investigators suggested the existence of gastric cancer stem cells (i.e., CD44+) and side population cells. These cells showed relative resistance to chemotherapy and radiation, and exclusive ability to initiate tumors. […]
#130 Etiopathogenesis and staging of gastric cancer | PPT
https://www.slideshare.net/slideshow/etiopathogenesis-and-staging-of-gastric-cancer/246553647
5. In terms of pathogenesis, two new concepts are worth mentioning: bone marrow participation in gastric carcinogenesis and gastric cancer stem cells. It has been hypothesized that the gastric epithelial cells acquiring abnormal phenotype (resembling intestinal epithelium) originate from gastric stem cells localized to the only cell replication zone of the gastric glands (i.e., the isthmus). […] […] 6. Although controversial, cancer stem cells are defined as cancer cells with the exclusive ability to initiate tumors, metastasize, and self-renew tumors. In gastric cancer, several investigators suggested the existence of gastric cancer stem cells (i.e., CD44+) and side population cells. These cells showed relative resistance to chemotherapy and radiation, and exclusive ability to initiate tumors. […]
#131 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, which chronically infects around half of all humans. […] An interdisciplinary research team at the Max Planck Institute in Berlin in collaboration with researchers in Stanford, California, has now discovered that the bacterium sends stem cell renewal in the stomach into overdrive and stem cell turnover has been suspected by many scientists to play a role in the development of cancer. […] They suspected that the answer might lie in the stem cells found at the bottom of the glands that line the inside of the stomach, which continually replace the remaining cells from the bottom up and which are the only long-lived cells in the stomach.
#132 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, which chronically infects around half of all humans. […] An interdisciplinary research team at the Max Planck Institute in Berlin in collaboration with researchers in Stanford, California, has now discovered that the bacterium sends stem cell renewal in the stomach into overdrive and stem cell turnover has been suspected by many scientists to play a role in the development of cancer. […] They suspected that the answer might lie in the stem cells found at the bottom of the glands that line the inside of the stomach, which continually replace the remaining cells from the bottom up and which are the only long-lived cells in the stomach.
#133 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
Gastric carcinoma is one of the most common causes of cancer-related deaths, primarily because most patients present at an advanced stage of the disease. The main cause of this cancer is the bacterium Helicobacter pylori, which chronically infects around half of all humans. […] An interdisciplinary research team at the Max Planck Institute in Berlin in collaboration with researchers in Stanford, California, has now discovered that the bacterium sends stem cell renewal in the stomach into overdrive and stem cell turnover has been suspected by many scientists to play a role in the development of cancer. […] They suspected that the answer might lie in the stem cells found at the bottom of the glands that line the inside of the stomach, which continually replace the remaining cells from the bottom up and which are the only long-lived cells in the stomach.
#134 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
They have now found that these stem cells do indeed respond to the infection by increasing their division producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients. […] Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. […] It is this signal, which turned out to control the response to H. pylori: Following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive. […] 'Our findings show that an infectious bacterium can increase stem cell turnover’, says Sigal. 'Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed,’ and Meyer adds: 'Our new findings shed light on the intriguing ways through which chronic bacterial infections disturb tissue function and provide invaluable clues on how bacteria, in general, may increase the risk of cancer’.
#135 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
They have now found that these stem cells do indeed respond to the infection by increasing their division producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients. […] Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. […] It is this signal, which turned out to control the response to H. pylori: Following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive. […] 'Our findings show that an infectious bacterium can increase stem cell turnover’, says Sigal. 'Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed,’ and Meyer adds: 'Our new findings shed light on the intriguing ways through which chronic bacterial infections disturb tissue function and provide invaluable clues on how bacteria, in general, may increase the risk of cancer’.
#136 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
They have now found that these stem cells do indeed respond to the infection by increasing their division producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients. […] Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. […] It is this signal, which turned out to control the response to H. pylori: Following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive. […] 'Our findings show that an infectious bacterium can increase stem cell turnover’, says Sigal. 'Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed,’ and Meyer adds: 'Our new findings shed light on the intriguing ways through which chronic bacterial infections disturb tissue function and provide invaluable clues on how bacteria, in general, may increase the risk of cancer’.
#137 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. […] These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis and immune surveillance. […] Helicobacter pylori infection is the major risk factor for gastric cancer and has been considered as a Group 1 carcinogen by the International Agency for Research on Cancer. […] Recent estimates show that 89% of all non-cardia tumors (about 780,000 cases) is attributable to H. pylori infection, making this bacterium responsible for at least 6.2% of all cancer cases worldwide.
#138 Clinical Pathogenesis, Molecular Mechanisms of Gastric Cancer Development | SpringerLink
https://link.springer.com/chapter/10.1007/978-3-031-47331-9_2
The human pathogen Helicobacter pylori is the strongest known risk factor for gastric disease and cancer, and gastric cancer remains a leading cause of cancer-related death across the globe. […] Carcinogenic mechanisms associated with H. pylori are multifactorial and are driven by bacterial virulence constituents, host immune responses, environmental factors such as iron and salt, and the microbiota. […] Infection with strains that harbor the cytotoxin-associated genes (cag) pathogenicity island, which encodes a type IV secretion system (T4SS) confer increased risk for developing more severe gastric diseases. […] Other important H. pylori virulence factors that augment disease progression include vacuolating cytotoxin A (VacA), specifically type s1m1 vacA alleles, serine protease HtrA, and the outer-membrane adhesins HopQ, BabA, SabA and OipA.
#139 Pathogenesis of gastric cancer: genetics and molecular classification
https://pmc.ncbi.nlm.nih.gov/articles/PMC8550817/
The mechanisms of malignant transformation mediated by H. pylori infection are discussed in chapters 2, 811 and 13. […] Epstein Barr virus (EBV) is considered to be a human carcinogen linked to development of several types of lymphoma and carcinoma, accounting for about 200,000 new cancer cases annually worldwide. […] Approximately 9% of gastric cancer cases have latent EBV infection in every tumor cell. […] EBV reactivation from latency is a postulated mechanism for the development of EBV-associated malignancies. […] Taken together, much has been learned about EBV-positive gastric cancer since it was first documented, but important knowledge gaps remain. […] It is still unclear when and how the virus appears in the gastric epithelium prior to tumor emergence. […] Elucidating the viral contribution to gastric cancer pathophysiology could lead to novel strategies for prevention and treatment, with possible extension to other EBV-related malignancies.
#140 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
To explore the new approaches to enhance the efficacy of H. pylori, a more comprehensive understanding of the molecular mechanisms by which H. pylori interacts with the host to facilitate gastric cancer development is crucial. Overall, this review is necessary as it will help us to pay more attention to the latest advances on the virulence and pathological mechanisms of H. pylori. […] The complex biological processes and molecular mechanisms behind gastric cancer pathogenesis remain unclear. Dysregulation of numerous pathways plays an important role during gastric carcinogenesis. The development of gastric cancer involves the following mechanisms that can activate the downstream signaling pathways, including the cytokine-stimulated transduction (JAK-STAT) signaling, the nuclear factor B (NF-B) pathway, the Wnt/-catenin signaling pathway, the mitogen-activated protein kinase (MAPK) pathway, the Hippo pathway, the PI3K/Akt pathway, and other signaling pathways. […] The molecular interplay between H. pylori and the host involves a sophisticated regulation of molecular mechanisms that contribute to gastric carcinogenesis.
#141 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#142 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis. […] Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs. […] H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes. […] The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis.
#143 Pathogenetic mechanisms in gastric cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC4194564/
Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs). Its overexpression has been reported in various human cancers, including GC. […] Many other molecular events are also found in gastric carcinogenesis. For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN). […] In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis. […] Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.
#144 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
Deregulation of cell apoptosis is a key event in H. pylori-induced gastric carcinogenesis, and H. pylori is capable of manipulating apoptosis in gastric epithelial cells to favor tumor survival and expansion. […] The inhibition of apoptosis is a critical molecular mechanism in carcinogenesis. H. pylori’s chronic infection and the resulting inflammatory state create a conducive environment for tumorigenesis. […] H. pylori employs additional strategies contributing to gastric cancer development, including interference with cell cycle progression and autophagy. […] The molecular mechanisms underlying H. pylori-promoted carcinogenesis are exceptionally intricate, involving the interplay of numerous pathways and interconnected links.
#145 Helicobacter pylori and gastric cancer: mechanisms and new perspectives | Journal of Hematology & Oncology | Full Text
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01654-2
NF-B is a key nuclear transcription factor in gastric carcinogenesis initiated by H. pylori. […] In conclusion, the NF-B pathway functions as a key effector in the development of H. pylori-mediated gastric cancer. It is not only involved in the manipulation of the immune responses but also directly drives various carcinogenic behaviors of tumor cells. […] Wnt/-catenin signaling pathway is a key regulatory mechanism in H. pylori-related gastric cancer. […] In conclusion, Wnt/-catenin signaling pathway is an important driving factor for the induction of gastric cancer by H. pylori, and this pathway plays a crucial role in various stages of carcinogenesis, including the early initiation and progression of gastric cancer. […] The chronic inflammatory response triggered by H. pylori is a significant risk factor for gastric carcinogenesis, involving complex interactions with other carcinogenic processes, such as oxidative stress and aberrant activation of cancer pathways. […] The chronic inflammatory response stimulated by H. pylori is a critical mechanism in gastric carcinogenesis. Inflammatory cells and their mediators are involved in multiple stages of gastric carcinogenesis, including DNA damage, gene mutation, and the formation of the tumor microenvironment.
#146 Molecular Mechanism for Malignant Progression of Gastric Cancer Within the Tumor Microenvironment
https://www.mdpi.com/1422-0067/25/21/11735
The TME of GC has great plasticity and undergoes continuous alterations and stage-specific modifications in response to various cancer cell-intrinsic and -extrinsic factors. Networks of cytokines and growth factors disrupt signaling pathways, and modified molecular signatures in the stroma characterize these changes in the TME. Previous efforts to characterize TME have underscored the pivotal role of the interaction between tumor cells and stroma in driving GC carcinogenesis, progression, and metastasis. […] CAFs are a main resource of the stroma and secrete soluble factors such as chemokines, cytokines, and growth factors to employ distinct cell types to the TME and reprogram them. CAFs also produce inflammatory ligands and ECM proteins, which in turn promote tumor growth, invasion, and migration of cancer cells, as well as immune evasion and resistance to anti-cancer therapies.
#147 Gastric cancer: Metabolic and metabolomics perspectives (Review)
https://www.spandidos-publications.com/10.3892/ijo.2017.4000
Up to now, several studies aimed at identifiable metabolic changes in macroenvironment-blood and urine or microenvironment-carcinoma tissues and gastric juice have been done to map globally metabolic profiles and interpret its possible mechanism in the process of gastric carcinogenesis. […] Altered metabolites in gastric can be categorized into four main biomolecules: carbohydrates, amino acids, lipids and nucleic acids. […] Activated glycolysis and impaired aerobic respiration shape the altered glucose metabolism in this disease. […] Elevated amino acids in microenvironment are contributing factors in carcinogenesis. […] Most strikingly, it is indicated that many cancer cell lines cannot survive in the absence of glutamine, because it is required for anabolic growth of mammalian cells through its ability to control the master regulator of protein translation mTORC1.
#148 Are stem cells the link between bacteria and cancer?
https://www.mpg.de/11437780/stomach-cancer-helicobacter-pylori-infection
They have now found that these stem cells do indeed respond to the infection by increasing their division producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients. […] Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. […] It is this signal, which turned out to control the response to H. pylori: Following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive. […] 'Our findings show that an infectious bacterium can increase stem cell turnover’, says Sigal. 'Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed,’ and Meyer adds: 'Our new findings shed light on the intriguing ways through which chronic bacterial infections disturb tissue function and provide invaluable clues on how bacteria, in general, may increase the risk of cancer’.
#149 Carcinoma Stomach: INTESTINAL VS DIFFUSE GASTRIC CANCER – Pathology Made Simple
https://ilovepathology.com/carcinoma-stomach-intestinal-vs-diffuse-gastric-cancer/
The key mechanism in diffuse type gastric cancer is the loss of a protein called E-cadherin. E-cadherin is responsible for cell adhesion, helping cells attach to one another. Loss of E-cadherin results in the dissociation of cells. This loss can occur due to mutations in the tumor suppressor gene called cdh1, which encodes E-cadherin. Additionally, hypermethylation and silencing of the cdh1 promoter region can also lead to the loss of E-cadherin. The loss of E-cadherin in diffuse type gastric cancer causes the infiltration of tumor cells throughout the gastric wall. This infiltration evokes a desmoplastic response, leading to stiffening of the stomach wall. The affected areas show diffuse rugal flattening and a rigid, thickened appearance resembling a leather bottle (linitis plastica) on imaging. Its important to note that diffuse type gastric cancer usually occurs sporadically, while intestinal type gastric cancer can be associated with H. pylori infection and specific dietary factors. Familial cases of gastric cancer are more commonly of the diffuse type.
#150 Molecular Pathogenesis of Gastric Adenocarcinoma | IntechOpen
https://www.intechopen.com/chapters/56242
Comprehensive understanding of the detailed molecular mechanisms and accurate pathogenesis of GC will improve patient outcome. Recently, several kinds of molecular classification of GC have been provided to reveal the genomic landscape of GC and decipher the crucial molecular changes. […] The Cancer Genome Atlas (TCGA) classification is a milestone for the molecular characterization of GC. […] The most highly transcribed EBV viral, message RNAs (mRNAs) and microRNAs (miRNAs), fell within the BamH1A region of the viral genome and showed similar expression patterns across tumors. […] The mutation rate of PIK3CA is exclusively high in EBV-positive gastric cancer compared with other molecular subtypes. […] The next subtypes of GC are abundant in MSI, which display increased mutation rates (in major histocompatibility complex class I genes, including B2M and HLA-B) and hypermethylation (containing hypermethylation at the MLH1 promoter).