Rak trzustki – Patofizjologia i mechanizm

Rak trzustki
Patofizjologia i mechanizm

Rak gruczołowy przewodowy trzustki (PDAC) stanowi około 90% nowotworów trzustki i charakteryzuje się bardzo niskim 5-letnim wskaźnikiem przeżycia poniżej 13%. Patogeneza PDAC obejmuje liczne zmiany genetyczne, w tym mutacje KRAS (90-95%), CDKN2A (95%), TP53 (50-75%) oraz utratę SMAD4, które prowadzą do zaburzeń cyklu komórkowego, genomowej niestabilności i przerzutów. Kluczowe szlaki sygnalizacyjne zaangażowane w rozwój i progresję PDAC to EGFR, PI3K/AKT (aktywność p-Akt w 46-70% przypadków), NF-κB, WNT oraz Hedgehog, które regulują proliferację, apoptozę, migrację i angiogenezę. Mikrośrodowisko guza, bogate w desmoplastyczne podścielisko i immunosupresyjne komórki, sprzyja progresji nowotworu i oporności na terapię. Metaboliczne przeprogramowanie komórek PDAC obejmuje glikolizę, metabolizm glutaminy, lipogenezę oraz autofagię, które umożliwiają adaptację do hipoksji i niedoboru składników odżywczych, co dodatkowo komplikuje leczenie.

Patogeneza raka trzustki

Zmiany molekularne w komórkach nowotworowych
Zderegulowane szlaki sygnałowe
Prekursory raka trzustki
Mikrośrodowisko guza trzustki
Zmiany metaboliczne w raku trzustki

Mechanizmy progresji i przerzutowania

Mechanizmy molekularne przerzutowania
Inwazja okołonerwowa
Komórki macierzyste raka

Oporność na leczenie

Mechanizmy oporności na leki
Rola autofagii

Znaczenie kliniczne i perspektywy terapeutyczne

Nowe cele terapeutyczne
Terapie celowane
Immunoterapia
Perspektywy badawcze
Kolejne rozdziały

Patogeneza raka trzustki

Rak gruczołowy przewodowy trzustki (PDAC – Pancreatic Ductal Adenocarcinoma) stanowi około 90% przypadków nowotworów trzustki i jest jednym z najbardziej śmiertelnych nowotworów o wyjątkowo niskim wskaźniku przeżycia 5-letniego, wynoszącym poniżej 13%¹². Jest to nowotwór klinicznie wymagający, zarówno ze względu na późne stadium rozpoznania, jak i oporność na chemioterapię. Pomimo postępów w zrozumieniu biologii PDAC, pacjenci wciąż odnoszą niewielkie korzyści z konwencjonalnych terapii³. Złożoność patogenezy raka trzustki obejmuje zarówno zmiany genetyczne, epigenetyczne i metaboliczne, jak również unikalne mikrośrodowisko guza.

Zmiany molekularne w komórkach nowotworowych

Rak trzustki charakteryzuje się rozległymi zmianami molekularnymi, w tym mutacjami somatycznymi, zmianami chromosomalnymi, modyfikacjami epigenetycznymi i przeprogramowaniem transkrypcyjnym⁴. Najczęstsze mutacje genowe w PDAC dotyczą protoonkogenu KRAS oraz genów supresorowych nowotworów: CDKN2A, TP53 i SMAD4⁵⁶.

Mutacje KRAS – występują w 90-95% przypadków PDAC i są jednym z najwcześniejszych zdarzeń w kancerogenezie trzustki. Prowadzą do konstytutywnej aktywacji szlaków sygnałowych KRAS, co skutkuje wzrostem komórek i rozwojem nowotworu⁷⁸.
Inaktywacja CDKN2A – występuje w około 95% przypadków i prowadzi do zaburzeń cyklu komórkowego⁹.
Mutacje TP53 – obecne w 50-75% przypadków, przyczyniają się do genomowej niestabilności i zaburzeń apoptozy¹⁰.
Utrata SMAD4 – występuje w późniejszym stadium choroby i jest związana z przerzutami. Powoduje zmniejszenie zależnej od SMAD4 inhibicji transformującego czynnika wzrostu beta (TGF-β) i promuje niekanoniczne sygnalizowanie TGF-β, co ułatwia odpowiedzi protumorogeniczne¹¹.

Oprócz mutacji w regionach kodujących, w PDAC wykryto również duże zmiany chromosomalne, w tym zmiany liczby kopii, rearanżacje chromosomalne i chromotrypsję¹²¹³.

Zderegulowane szlaki sygnałowe

W patogenezie raka trzustki istotną rolę odgrywają szlaki sygnalizacyjne, w tym EGFR, PI3K/AKT, NF-κB, JAK/STAT, Hippo/YAP, WNT i inne¹⁴. Ich deregulacja przyczynia się do procesów komórkowych związanych z nowotworami, takich jak proliferacja, różnicowanie, apoptoza, migracja, angiogeneza, metabolizm i regulacja immunologiczna.

Szlak EGFR – zmiany genomowe EGFR w rakach obejmują nadekspresję, mutację, delecję i rearanżację. Zmiany te indukują aktywność kinaz receptorowych tyrozynowych i mogą promować rozwój i progresję raka trzustki¹⁵.
Szlak PI3K/AKT – znaczna część (46-70%) raków trzustki wykazuje wysokie poziomy p-Akt, co koreluje z wysokim stopniem złośliwości guza i złym rokowaniem¹⁶.
Szlak NF-κB – jest konstytutywnie aktywowany w większości ludzkich tkanek raka trzustki i linii komórkowych, ale nie w normalnych tkankach i komórkach trzustki, sugerując, że aktywacja NF-κB jest zaangażowana w kancerogenezę raków trzustki¹⁷.
Szlak WNT – zarówno kanoniczny (β-kateninozależny), jak i niekanoniczny (β-katenino-niezależny) szlak zostały powiązane z kancerogenezą trzustki, progresją guza i opornością terapeutyczną¹⁸.
Szlak Hedgehog (Hh) – jest kluczowy dla rozwoju raka trzustki poprzez różne mechanizmy, w tym aktywację fibroblastów związanych z rakiem (CAFs), regulację przeżycia i wzrostu komórek guza oraz oddziaływanie na mikrośrodowisko guza¹⁹.

Komórki bez mutacji KRAS mogą wykazywać aktywację RAS poprzez sygnalizowanie upstream przez receptory kinaz tyrozynowych (RTK), np. receptor naskórkowego czynnika wzrostu (EGFR), a onkogenna aktywacja cząsteczki B-RAF jest wykrywana u niewielkiej liczby pacjentów²⁰.

Prekursory raka trzustki

Rak trzustki powstaje z nieinwazyjnych prekursorowych zmian, które są uleczalne, jeśli zostaną wystarczająco wcześnie wykryte i leczone²¹. Większość PDAC wywodzi się z mikroskopowych śródnabłonkowych neoplazji trzustki (PanIN), neoplazmu obejmującego przewody trzustkowe²²²³.

Rozwój i progresja raka trzustki to proces wieloetapowy. Rak trzustki postępuje od nienowotworowych zmian prekursorowych zwanych śródnabłonkowymi neoplazjami trzustki (PanIN) do inwazyjnego raka²⁴. Liczne zmiany genetyczne gromadzą się z czasem i napędzają progresję histologiczną przez etapy PanIN (PanIN1-3), prowadząc ostatecznie do inwazyjnego gruczolakoraka²⁵.

W kontekście progresji do PDAC, każdy etap PanIN jest związany z coraz częstszymi modyfikacjami w kanonicznych onkogenach i genach supresorowych guza, takich jak Ki-RAS (90-100%), p16/CDKN2A (90-95%), p53 (50-85%), DPC4/SMAD4 (50%) i BRCA2 (10%)²⁶.

Mikrośrodowisko guza trzustki

Mikrośrodowisko guza (TME) odgrywa kluczową rolę w patogenezie raka trzustki i niepowodzeniu interwencji terapeutycznych²⁷. Rak trzustki charakteryzuje się gęstym desmoplatycznym podścieliskiem wytwarzanym przez fibroblasty związane z rakiem (CAFs)²⁸.

Podścielisko desmoplatyczne – w raku trzustki nadmierna reakcja desmoplastyczna indukuje proliferację komórek fibroblastów i produkcję macierzy pozakomórkowej (ECM)²⁹. Macierz zewnątrzkomórkowa tworzy włóknistą siatkę wokół komórek guza, a wykazano, że kwas hialuronowy (HA), główny składnik ECM, zapewnia korzystne mikrośrodowisko dla progresji raka trzustki, promując proliferację komórek złośliwych, agresywność i oporność na terapię przeciwnowotworową, co skutkuje złym rokowaniem³⁰.
Immunosupresja – PDAC wykazuje liczne zmiany w podtypach komórek immunologicznych, co prowadzi do immunosupresyjnego mikrośrodowiska³¹. Zmiany te obejmują zwiększenie liczby immunosupresyjnych komórek T regulatorowych i komórek supresorowych pochodzenia szpikowego, zapobiegając zwalczaniu komórek nowotworowych przez układ odpornościowy³².
Fibroblasty związane z rakiem (CAFs) – komórki rakowe przebudowują otaczające podścielisko podczas złośliwej progresji i rozwijają wzajemne połączenie z otaczającym podścieliskiem, aby wspólnie promować własny wzrost³³. Interakcja między CAFs a komórkami raka trzustki jest znacząco wpływana przez szlak sygnalizacyjny Wnt/β-katenina, który wydziela ligandy Wnt i aktywuje receptory Frizzled na komórkach guza oraz szlak sygnalizacyjny β-kateniny³⁴.
Cytokiny – wydzielane przez CAFs cytokiny, takie jak IL-6 i IL-11, aktywują receptory zlokalizowane na powierzchni komórek guza, promując szlak sygnalizacyjny JAK/STAT. Ta aktywacja wspiera przeżycie, proliferację i inwazję komórek guza³⁵.

Mikrośrodowisko guza w raku trzustki jest wysoce immunosupresyjne i charakteryzuje się obfitą odpowiedzią stromalną jako reakcją desmoplastyczną³⁶. Interakcja między komórkami guza a mikrośrodowiskiem stromalnym jest złożona, a elementy stromalne regulują progresję raka trzustki w bardziej złożony sposób³⁷.

Zmiany metaboliczne w raku trzustki

Zaburzenia metaboliczne są jednym z charakterystycznych cech raka trzustki. Komórki raka trzustki mogą adaptować się do biosyntezy, pobierania energii i potrzeb redoksowych poprzez przeprogramowanie metaboliczne, aby tolerować niedobór składników odżywczych i hipoksyczne mikrośrodowiska³⁸.

Glikoliza – jest to jeden z głównych szlaków metabolicznych dostarczających energii komórkom nowotworowym trzustki.
Metabolizm glutaminy – komórki PDAC wykorzystują enzym glutaminazę do przekształcania aminokwasu glutaminianu w glutaminę, która może być spalana jako paliwo do podtrzymania szybkiego wzrostu guza³⁹.
Metabolizm lipidów – regulacja lipogenezy de novo zachodzi głównie na poziomie transkrypcji, a białka wiążące element regulacyjny sterolu (SREBP) mogą regulować geny związane z syntezą kwasów tłuszczowych i cholesterolu oraz ich pobieraniem⁴⁰. Cholesterol odgrywa kluczową rolę w utrzymaniu integralności i płynności błony oraz regulacji zdarzeń sygnalizacyjnych komórek⁴¹.
Oksydacja kwasów tłuszczowych (FAO) – znana również jako β-oksydacja, jest zwiększona w wielu komórkach nowotworowych, ponieważ komórki nowotworowe mogą wykorzystywać katabolizm kwasów tłuszczowych (FA) do proliferacji, gdy ATP jest wyczerpany⁴².

Aby przystosować się do trudnych warunków, komórki PDAC polegają na lizosomach do degradacji i regeneracji składników odżywczych, takich jak poprzez makropinocytozę i autofagię, aby uzyskać wystarczającą ilość paliwa do przeżycia⁴³. Badania wykazały, że autofagia promuje ucieczkę immunologiczną w PDAC poprzez degradację MHC-I oraz że połączenie inhibicji MEK i autofagii może hamować PDAC⁴⁴.

Mechanizmy progresji i przerzutowania

Rak trzustki jest ogólnie uważany za niezwykle agresywny nowotwór o wysokiej skłonności do przerzutów⁴⁵. Wykazano, że przerzuty mogą wystąpić już we wczesnych stadiach raka trzustki, nawet przed utworzeniem dużej masy przez guz pierwotny⁴⁶.

Mechanizmy molekularne przerzutowania

Badacze odkryli, że komórki nowotworowe osiągają zdolność do przerzutowania poprzez epigenetyczne przeprogramowanie wzmacniaczy genów, które przywraca je do wcześniejszego stanu rozwojowego charakteryzującego się proliferacją i zwiększoną mobilnością⁴⁷. Zespół Vakoca dostarczył dowodów na epigenetyczne podłoże przerzutów⁴⁸.

„Tworzenie guza jest napędzane przez zdarzenia genetyczne, ale jego zdolność do rozprzestrzeniania się może nie obejmować bezpośrednich zmian w sekwencji DNA” – wyjaśnia dr Roe⁴⁹. W porównaniu z komórkami w nienowotworowych i guzopodobnych organoidach, te w przerzutowych wykazywały nadzwyczajną liczbę zmian w regionach zwanych wzmacniaczami⁵⁰.

Aktywacja FOXA1, indukująca przeprogramowanie wzmacniacza, które wyposaża komórkę nowotworową we właściwości przerzutowe, jest mechanizmem epigenetycznym, a nie genetycznym, który wyjaśnia przynajmniej jeden mechanizm przerzutów w tej postaci raka trzustki i prawdopodobnie także w innych typach raka⁵¹.

Inwazja okołonerwowa

Inwazja okołonerwowa jest charakterystyczną cechą raka trzustki i często pierwszą drogą przerzutów prowadzącą do bólu neuropatycznego⁵². Inwazja pozatrzustkowego splotu nerwowego jest odpowiedzialna za odczucie bólu neuropatycznego⁵³.

Podobieństwa w receptorach czynników wzrostu i cząsteczkach adhezyjnych między komórkami raka trzustki a komórkami neuronalnymi wyjaśniają powinowactwo do tkanki nerwowej i prowadzą do zwiększonej proliferacji komórek nowotworowych oraz migracji i inwazji wzdłuż pęczków nerwowych⁵⁴. Migracja komórek raka trzustki wzdłuż pęczków nerwowych powoduje ból neuropatyczny, zwiększoną neuroplastyczność i odczuwanie bólu w odpowiedzi na stymulację wzrostu włókien czuciowych⁵⁵.

Molekularny mechanizm inwazji okołonerwowej (PNI) jest skomplikowany, głównie obejmuje neurotrofiny i ich receptory (np. czynnik wzrostu nerwów [NGF]), proteinazy (metaloproteinazy [MMP]), cytokiny (np. transformujący czynnik wzrostu [TGF], nabłonkowy czynnik wzrostu [EGFR]), chemokiny (np. CX3CL1, CX3CR1) i markery powierzchni komórek (np. MUC1, NCAM)⁵⁶.

Komórki macierzyste raka

Komórki macierzyste raka (CSC) stanowią 0,2-0,8% komórek raka trzustki i są uważane za odpowiedzialne za wzrost guza, inwazję, przerzuty i nawrót⁵⁷. Kilka badań sugeruje, że komórki macierzyste raka nie mogą być wyeliminowane przez obecną terapię i w związku z tym są odpowiedzialne za nawrót guza i przerzuty⁵⁸.

Obecność komórek macierzystych raka została opisana w 2007 roku przez Shaha i wsp., którzy wykazali, że komórki CD44+CD24+ESA+ wykazują wysoki potencjał nowotworowy⁵⁹. Oporność CSC została wyjaśniona kilkoma mechanizmami: (1) ekspresją genów związanych z wielolekowymi opornościami, głównie transporterami leków ATP-wiążącymi (ABC); (2) aktywacją sygnalizacji Wnt/β-kateniny; oraz (3) aktywacją szlaku Hedgehog⁶⁰.

Rozwojowa zmiana komórek PDAC z fenotypu nabłonkowego na mezenchymalny lub fibroblastoidalny (przejście epitelialno-mezenchymalne, EMT) jest uważana za kluczowy krok w progresji guzów pierwotnych do inwazyjnych/przerzutowych/lekoopornych⁶¹.

Oporność na leczenie

Wysoki wskaźnik śmiertelności raka trzustki wynika z trudności we wczesnym rozpoznaniu i jego notorycznej oporności na chemioterapię i radioterapię⁶². Dane sekwencjonowania ujawniły, że rak trzustki składa się z wysoce heterogennych guzów, które rozwijają oporność na tradycyjną chemioterapię i radioterapię⁶³.

Mechanizmy oporności na leki

Chemooporność jest krytycznym problemem w raku trzustki. Wśród mechanizmów odpowiedzialnych za oporność na leki, najbardziej istotne są zmiany w poszczególnych genach lub szlakach sygnałowych, wpływ wywierany przez mikrośrodowisko guza (reakcja desmoplastyczna) oraz obecność wysoce opornych komórek macierzystych raka (CSC)⁶⁴.

Guzy trzustki są znane z ich oporności na chemioterapię, częściowo z powodu ich gęstej, słabo unaczynionej struktury tkankowej, która tworzy obszary niskiego stężenia tlenu (hipoksji) w guzie⁶⁵. Badacze wykazali, że hipoksja faktycznie przesuwa komórki raka trzustki w bardziej agresywny, chemooporny stan⁶⁶.

Badanie opublikowane w Cancer Research ujawniło, że gdy komórki raka trzustki są pozbawione tlenu, w komórkach aktywowany jest specyficzny proces. Proces ten obejmuje zmiany w sposobie modyfikacji materiału genetycznego komórek i sposobie wysyłania sygnałów w komórce, co sprawia, że komórki nowotworowe stają się silniejsze i bardziej odporne na chemioterapię⁶⁷.

Rola autofagii

Autofagia, lizosomalno-mediowany, wysoce zachowany proces degradacji, który usuwa nieprawidłowe białka i uszkodzone organelle z organizmu, jest zwiększona w gruczolakoraku przewodowym trzustki⁶⁸. W początkowej fazie autofagia hamuje przekształcanie przedrakowych zmian w raka. Jednak w stadium postępującym autofagia promuje wzrost guza. Autofagia jest również jednym z głównych mechanizmów oporności na leki podczas leczenia⁶⁹.

Autofagia reguluje stan zapalny podczas patogenezy PDAC. Badania wykazały, że knockout genów związanych z autofagią (ATG5 lub ATG7) lub białek kodujących funkcję lizosomalną LAMP2 prowadzi do ciężkiej degeneracji komórek pęcherzykowych, zaniku trzustki, włóknienia i stanu zapalnego⁷⁰.

Autofagia może hamować patogenezę PDAC, ale może dostarczać energii dla komórek, promując początek PDAC, gdy komórki trzustki mają rakotwórcze mutacje KRAS⁷¹. W komórkach PDAC występuje zwiększone niszczenie mitochondriów w porównaniu z normalnymi komórkami. Dla homeostazy komórkowej istotne jest utrzymanie zdrowych mitochondriów, w tym ich ilości i jakości⁷².

Znaczenie kliniczne i perspektywy terapeutyczne

Wysoka częstość występowania mutacji KRAS (noszona przez 90% pacjentów z rakiem trzustki) doprowadziła do znacznego zainteresowania terapiami ukierunkowanymi na KRAS⁷³. Głębsze zrozumienie biologii i genetyki raka trzustki, w tym nowy wgląd w mutacje genów napędzających, metabolizm guza i mikrośrodowisko guza, może prowadzić do obiecujących i innowacyjnych strategii terapeutycznych⁷⁴.

Nowe cele terapeutyczne

Ukierunkowanie na kluczowe enzymy w szlakach metabolicznych może wpływać na progresję raka trzustki⁷⁵. Adaptacja komórek PDAC do niedoboru składników odżywczych jest odwracalna, a syntetaza glutaminowa (GS) ma szansę stać się celem terapeutycznym dla pacjentów z PDAC⁷⁶.

Wiele badań wykazało, że inne aminokwasy, takie jak seryna, tryptofan, metionina i aminokwasy rozgałęzione (BCAA), takie jak leucyna, odgrywają rolę w różnych stadiach guzów i mają szansę rozwinąć nowe strategie interwencyjne⁷⁷.

Terapie celowane

Inhibitory PARP (PARPi) mogą wiązać się z kieszenią wiążącą NAD+ PARP-1, powodować zmiany konformacyjne w PARP-1 i stabilizować połączenie PARP-1 i DNA. Jest to określane jako pułapka kompleksów DNAPARP-1⁷⁸. Wynika z tego, że PARPi mogą powodować głębokie uszkodzenie naprawy SSB, podczas gdy naprawa DSB odgrywa kluczową rolę w utrzymaniu integralności materiału genetycznego, który z kolei wykorzystuje HRR jako optymalny szlak kompensacyjny⁷⁹.

Jedynym zaakceptowanym PARPi do zastosowania klinicznego w raku trzustki jest olaparib. Zgodnie z badaniem POLO, został on zastosowany jako monoterapia w leczeniu podtrzymującym u pacjentów z przerzutowym rakiem trzustki, którzy nie wykazują progresji choroby przez 16 tygodni po chemioterapii pierwszej linii na bazie platyny⁸⁰.

Immunoterapia

Rak trzustki, jeden z najbardziej śmiertelnych spośród wszystkich nowotworów, jest zdolny do unikania ataków komórek immunologicznych poprzez zmianę swojego mikrośrodowiska w taki sposób, że komórki immunologiczne raczej hamują, niż wspierają atak na guz⁸¹.

Jednym z powodów tej oporności na leczenie jest mikrośrodowisko guza PDAC, które aktywnie tłumi odpowiedzi immunologiczne, które są pomocne w atakowaniu komórek nowotworowych⁸². Złośliwe komórki trzustki jednocześnie próbują znaleźć sposoby na uniknięcie ataku limfocytów T poprzez wpływanie na składniki mikrośrodowiska guza, aby sprzyjać rozwojowi i wzrostowi raka, proces nazywany przebudową⁸³.

Oprócz odkrycia przebudowy i unikania, zespół badawczy był w stanie ustalić, że jednym z mediatorów tej odpowiedzi supresyjnej było aktywowane białko zwane przekaźnikiem sygnału i aktywatorem transkrypcji 1 (STAT1)⁸⁴. Naukowcy postawili hipotezę, że sygnalizowanie oparte na STAT1 mogłoby być celem dla odwrócenia tego mechanizmu oporności⁸⁵.

Perspektywy badawcze

Badania nad patogenezą raka trzustki koncentrują się obecnie na wielu obiecujących kierunkach:

Metabolizm systemowy – poza lokalnym przeprogramowaniem metabolicznym w guzach, metabolizm systemowy może również służyć jako potencjalny mechanizm patogenetyczny i cel terapeutyczny⁸⁶.
Zespół metaboliczny (MetS) – stan patologiczny charakteryzujący się otyłością brzuszną, insulinoopornością, nadciśnieniem i hiperlipidemią, jest związany z ryzykiem PDAC⁸⁷.
Autofagia – badania na myszach z defektem autofagii sugerują, że proces autofagii może być skutecznym celem interwencji w zapobieganiu i leczeniu raka trzustki⁸⁸. Hamowanie autofagii może być ważnym kierunkiem terapii celowanej dla raka trzustki w przyszłości, a rozwój i stosowanie inhibitorów autofagii powinno być priorytetem⁸⁹.
Wczesna diagnostyka – zdolność do zakłócania trwałych, indukowanych hipoksją zmian w komórkach raka trzustki oferuje potencjalny przełom w poprawie wyników pacjentów⁹⁰. Ukierunkowanie na szlaki, które umożliwiają komórkom nowotworowym opieranie się chemioterapii, może przynieść nowe, bardziej skuteczne metody leczenia dla pacjentów z rakiem trzustki⁹¹.

Podsumowując, patogeneza raka trzustki obejmuje złożoną sieć zmian genetycznych, epigenetycznych, metabolicznych i oddziaływań z mikrośrodowiskiem guza. Postępy w zrozumieniu tych mechanizmów otwierają drogę do nowych podejść diagnostycznych i terapeutycznych, które mogą przyczynić się do poprawy rokowania w tej wciąż bardzo śmiertelnej chorobie.

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Pancreatic cancer (PC), is an aggressive cancer with a poor prognosis. […] The overall five-year survival rate is less than 13%, and it is expected that PC will rank second in malignant tumour-related deaths in the United States by 2030. […] Targeting key enzymes in metabolic pathways can affect the progression of pancreatic cancer. […] The complex tumor microenvironment of pancreatic cancer creates metabolic heterogeneity. […] Clinical trials exploring metabolic-based treatments for pancreatic cancer have been initiated. […] Systemic metabolism can also serve as a potential pathogenic mechanism and therapeutic target. […] The adaptation of PDAC cells to nutrient deprivation is reversible, and glutamine synthetase (GS) is expected to become a therapeutic target for patients with PDAC.
#2 Pancreatic Cancer: Pathogenesis, Prevention and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC2094388/
Pancreatic cancer is the fourth leading cause of cancer death in the United States with a very low survival rate of 5 years. To better design new preventive and/or therapeutic strategies for the fight against pancreatic cancer, the knowledge of the pathogenesis of pancreatic cancer at the molecular level is very important. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways among which the EGFR, Akt, and NF-B pathways appear to be most relevant. […] The activation of oncogenes and the inactivation of tumor suppressor genes are partly responsible for the initiation and progression of pancreatic cancers. […] Moreover, the deregulation of molecules in several cell signaling pathways, such as EGFR, Akt, NF-B, etc, and their molecular crosstalk also play important roles in the molecular pathogenesis of pancreatic cancer.
#3 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. […] Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. […] In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. […] Approximately 90% of pancreatic cancers are characterized as pancreatic ductal adenocarcinoma (PDAC). […] Advances in next-generation genome sequencing (NGS) have brought new excitement to the field by supporting the identification of molecular alterations that govern pancreatic cancer progression.
#4 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
PDACs exhibit multiple alterations to immune cell subtypes, resulting in an immunosuppressive or cold microenvironment. […] These alterations include increased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, preventing immune-mediated targeting of cancer cells. […] PDACs have a dense desmoplastic stroma that is produced by cancer-associated fibroblasts (CAFs). […] PDAC is characterized by extensive molecular alterations, including somatic mutations, chromosomal alterations, epigenetic modifications, and transcriptional reprogramming, all occurring in tumor cells.
#5 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
Although the pathological features of these precancers are well characterized, the cell of origin of pancreatic cancer remains controversial. […] PDAC is caused, at least in part, by somatic mutations in oncogenes and tumor suppressor genes. […] The most commonly mutated genes in PDAC, the oncogene KRAS and the tumor suppressor genes CDKN2A, TP53, and SMAD4, were originally discovered in the 1980s and 1990s through targeted molecular biology and sequencing approaches. […] In addition to small somatic mutations involving coding regions, the expansion of PDAC genomic analysis to include whole genome sequencing has also catalogued large chromosomal alterations, including copy number alterations, chromosomal rearrangements, and chromothripsis. […] Pathologically, PDAC consists of malignant glands with haphazard architecture embedded in a dense desmoplastic stroma.
#6 Pancreatic cancer – Wikipedia
https://en.wikipedia.org/wiki/Pancreatic_cancer
The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4 (55%). The last of these is especially associated with a poor prognosis. […] Pancreatic ductal adenocarcinoma cancer cells are known to secrete immunosuppressive cytokines, creating a tumor microenvironment that inhibits immune detection and blocks anti-cancer immunity. Cancer associated fibroblasts secrete fibrous tissue (desmoplasia) consisting of matrix metalloproteinases and hyaluronan which blocks the host’s CD8+ T-cells from reaching the tumor. Tumor associated macrophages, neutrophils and regulatory T-cells secrete cytokines and work to create a tumor microenvironment that promotes cancer growth.
#7 Molecular pathogenesis of exocrine pancreatic cancer – UpToDate
https://www.uptodate.com/contents/molecular-pathogenesis-of-exocrine-pancreatic-cancer
The molecular pathogenesis of exocrine pancreatic cancer is presented here. Familial risk factors for pancreatic cancer are presented separately. […] As a general rule, multiple combinations of molecular alterations are commonly found in pancreatic adenocarcinomas. These can be divided into several broad categories: […] Oncogenes â Activation of oncogenes such as KRAS. […] Tumor suppressor genes â Inactivation of tumor suppressor genes such as TP53, p16/cyclin-dependent kinase inhibitor 2A (CDKN2A), and SMAD4.
#8 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Oncogenic KRAS has been extensively studied in PC because of the high prevalence of its mutations. […] Mutated KRAS results in the constitutive activation of its downstream oncogenic signaling. It has been suggested that oncogenic KRAS signaling is required for initiation, progression and maintenance of PC. […] The TP53 gene, located on chromosome 17p, is reported to be mutated in ~50â75% of PC patients. […] The altered p53 gene may give rise to a distinct pancreatic tumor morphology via coupling with other genetic abnormalities. […] SMAD4 is another tumor suppressor protein that transduces extracellular signals of transforming growth factor-beta (TGF-Î²) to the nucleus by acting as a transcriptional regulator. […] Loss of SMAD4 occurs at a later stage of disease and has been associated with tumor metastases in PC.
#9 Pancreatic cancer – Wikipedia
https://en.wikipedia.org/wiki/Pancreatic_cancer
The genetic events found in ductal adenocarcinoma have been well characterized, and complete exome sequencing has been done for the common types of tumor. Four genes have each been found to be mutated in the majority of adenocarcinomas: KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%), and SMAD4 (55%). The last of these is especially associated with a poor prognosis. […] Pancreatic ductal adenocarcinoma cancer cells are known to secrete immunosuppressive cytokines, creating a tumor microenvironment that inhibits immune detection and blocks anti-cancer immunity. Cancer associated fibroblasts secrete fibrous tissue (desmoplasia) consisting of matrix metalloproteinases and hyaluronan which blocks the host’s CD8+ T-cells from reaching the tumor. Tumor associated macrophages, neutrophils and regulatory T-cells secrete cytokines and work to create a tumor microenvironment that promotes cancer growth.
#10 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Oncogenic KRAS has been extensively studied in PC because of the high prevalence of its mutations. […] Mutated KRAS results in the constitutive activation of its downstream oncogenic signaling. It has been suggested that oncogenic KRAS signaling is required for initiation, progression and maintenance of PC. […] The TP53 gene, located on chromosome 17p, is reported to be mutated in ~50â75% of PC patients. […] The altered p53 gene may give rise to a distinct pancreatic tumor morphology via coupling with other genetic abnormalities. […] SMAD4 is another tumor suppressor protein that transduces extracellular signals of transforming growth factor-beta (TGF-Î²) to the nucleus by acting as a transcriptional regulator. […] Loss of SMAD4 occurs at a later stage of disease and has been associated with tumor metastases in PC.
#11 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
Sequencing data have revealed that pancreatic cancer comprises highly heterogeneous tumors that develop resistance to traditional chemotherapy and radiation therapy. […] It is evident that KRAS mutation seems to be necessary but not sufficient for pancreatic cancer development. […] Other genes, including tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4), are also frequently involved in pancreatic cancer tumorigenesis and metastasis. […] In pancreatic cancer, the frequent loss of SMAD4 via homozygous deletion or mutation leads to decreasing SMAD4-dependent inhibition of transforming growth factor- (TGF-) and the promotion of noncanonical TGF- signaling, thereby facilitating pro-tumorigenic responses. […] Signaling pathways (e.g., RAS, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), janus kinase (JAK)/signal transducer and activator of transcription (STAT), Hippo/yes-kinase-associated-protein (YAP), Wingless/int1 (WNT), etc.) have been linked to a variety of cancer-related cellular processes, including cell proliferation, differentiation, apoptosis, migration, angiogenesis, metabolism, and immune regulation.
#12 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
Although the pathological features of these precancers are well characterized, the cell of origin of pancreatic cancer remains controversial. […] PDAC is caused, at least in part, by somatic mutations in oncogenes and tumor suppressor genes. […] The most commonly mutated genes in PDAC, the oncogene KRAS and the tumor suppressor genes CDKN2A, TP53, and SMAD4, were originally discovered in the 1980s and 1990s through targeted molecular biology and sequencing approaches. […] In addition to small somatic mutations involving coding regions, the expansion of PDAC genomic analysis to include whole genome sequencing has also catalogued large chromosomal alterations, including copy number alterations, chromosomal rearrangements, and chromothripsis. […] Pathologically, PDAC consists of malignant glands with haphazard architecture embedded in a dense desmoplastic stroma.
#13 Pancreatic Cancer: Updates in Pathogenesis and Therapies | IntechOpen
https://www.intechopen.com/chapters/88046
Despite the progress in pancreatic cancer (PC) chemo/radiotherapies, immunotherapies, and novel targeted therapies and the improvement in its peri-operative management policies, it still has a dismal catastrophic prognosis due to delayed detection, early neural and vascular invasions, early micro-metastatic spread, tumour heterogeneities, drug resistance either intrinsic or acquired, unique desmoplastic stroma, and tumour microenvironment (TME). […] Understanding PDAC pathogenesis at the detailed genetic/epigenetic/metabolic/molecular levels as a tool to reach a more successful therapy for this challenging tumour remains an area of continuous aggressive research. The targeted molecular biology, whole exome sequencing studies, and genomic analyses showed that PDAC may occur due to mutational activation of some oncogenes/proto-oncogenes (i.e. KRAS, c-Myc, PAK4, MYB, HER2, etc.) and/or inactivation of some tumour suppressor genes (i.e. p16, TP53, SMAD4, CDKN2A, etc.), and/or mutations of DNA damage/repair (DDR) genes (i.e. ATM, BRCA1, BRCA2, PALB2, STK11, etc.), moreover, they can come from large chromosomal alterations (copy number alterations, chromosomal rearrangements, chromosomal instability from telomeres shortening, and clustered genomic rearrangements (chromothripsis)).
#14 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
Sequencing data have revealed that pancreatic cancer comprises highly heterogeneous tumors that develop resistance to traditional chemotherapy and radiation therapy. […] It is evident that KRAS mutation seems to be necessary but not sufficient for pancreatic cancer development. […] Other genes, including tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4), are also frequently involved in pancreatic cancer tumorigenesis and metastasis. […] In pancreatic cancer, the frequent loss of SMAD4 via homozygous deletion or mutation leads to decreasing SMAD4-dependent inhibition of transforming growth factor- (TGF-) and the promotion of noncanonical TGF- signaling, thereby facilitating pro-tumorigenic responses. […] Signaling pathways (e.g., RAS, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), janus kinase (JAK)/signal transducer and activator of transcription (STAT), Hippo/yes-kinase-associated-protein (YAP), Wingless/int1 (WNT), etc.) have been linked to a variety of cancer-related cellular processes, including cell proliferation, differentiation, apoptosis, migration, angiogenesis, metabolism, and immune regulation.
#15 Pancreatic Cancer: Pathogenesis, Prevention and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC2094388/
The genomic alterations of EGFR that occur in cancers include over-expression, mutation, deletion, and rearrangement. These alterations of EGFR induce the activity of receptor tyrosine kinases and may promote the development and progression of pancreatic cancer. […] It has been found that a significant proportion (4670%) of pancreatic cancer has high levels of p-Akt, which is correlated with high tumor grade and poor prognosis. […] NF-B is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and cells, suggesting that the activation of NF-B is involved in the carcinogenesis of pancreatic cancers. […] The deregulation of other signaling pathways (i.e. STAT3, MAPK, VEGF, IGF, etc) also plays roles in the development and progression of pancreatic cancer. Therefore, oncogenes, tumor suppressor genes, and the complex interactions between many cellular signaling pathways make up a network whose crosstalk contributes to the molecular pathogenesis of pancreatic cancer, suggesting that targeted inactivation of these important signaling pathways could be a novel and newer approach for the prevention and/or treatment of pancreatic cancer.
#16 Pancreatic Cancer: Pathogenesis, Prevention and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC2094388/
The genomic alterations of EGFR that occur in cancers include over-expression, mutation, deletion, and rearrangement. These alterations of EGFR induce the activity of receptor tyrosine kinases and may promote the development and progression of pancreatic cancer. […] It has been found that a significant proportion (4670%) of pancreatic cancer has high levels of p-Akt, which is correlated with high tumor grade and poor prognosis. […] NF-B is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and cells, suggesting that the activation of NF-B is involved in the carcinogenesis of pancreatic cancers. […] The deregulation of other signaling pathways (i.e. STAT3, MAPK, VEGF, IGF, etc) also plays roles in the development and progression of pancreatic cancer. Therefore, oncogenes, tumor suppressor genes, and the complex interactions between many cellular signaling pathways make up a network whose crosstalk contributes to the molecular pathogenesis of pancreatic cancer, suggesting that targeted inactivation of these important signaling pathways could be a novel and newer approach for the prevention and/or treatment of pancreatic cancer.
#17 Pancreatic Cancer: Pathogenesis, Prevention and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC2094388/
The genomic alterations of EGFR that occur in cancers include over-expression, mutation, deletion, and rearrangement. These alterations of EGFR induce the activity of receptor tyrosine kinases and may promote the development and progression of pancreatic cancer. […] It has been found that a significant proportion (4670%) of pancreatic cancer has high levels of p-Akt, which is correlated with high tumor grade and poor prognosis. […] NF-B is constitutively activated in most human pancreatic cancer tissues and cell lines but not in normal pancreatic tissues and cells, suggesting that the activation of NF-B is involved in the carcinogenesis of pancreatic cancers. […] The deregulation of other signaling pathways (i.e. STAT3, MAPK, VEGF, IGF, etc) also plays roles in the development and progression of pancreatic cancer. Therefore, oncogenes, tumor suppressor genes, and the complex interactions between many cellular signaling pathways make up a network whose crosstalk contributes to the molecular pathogenesis of pancreatic cancer, suggesting that targeted inactivation of these important signaling pathways could be a novel and newer approach for the prevention and/or treatment of pancreatic cancer.
#18 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
RAS signaling appears to play a critical role in both pancreatic cancer initiation and maintenance. […] Pancreatic cancers without KRAS mutations show RAS activation via upstream signaling through receptor tyrosine kinases (RTKs), e.g., epidermal growth factor receptor (EGFR), and oncogenic activation of the downstream B-Raf proto-oncogene (B-RAF) molecule is detected in a small number of patients. […] The WNT signaling pathway includes the canonical and noncanonical pathways and controls the maintenance of somatic stem cells in many tissues. […] Both the canonical (-catenin-dependent) and noncanonical (-catenin-independent) pathways have been implicated in pancreatic carcinogenesis, tumor progression, and therapeutic resistance. […] Pancreatic cancer is generally considered an extremely aggressive tumor with high metastatic propensity.
#19 Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways
https://www.wjgnet.com/2218-4333/full/v16/i2/97007.htm
The TGF- signaling pathway also plays a crucial role in modulating the efficacy of chemotherapeutic drugs for pancreatic cancer. An in-depth study of the complex role of TGF- signaling in pancreatic cancer development is essential for the advancement of targeted treatment approaches. […] The Hh signaling pathway is crucial for pancreatic cancer development through various mechanisms, including the activation of CAFs, the regulation of tumor cell survival and growth, and the TME. These studies help elucidate the pathophysiology of pancreatic cancer and provide a scientific basis for developing anticancer strategies targeting the Hh pathway. […] The interaction between CAFs and pancreatic cancer cells is significantly influenced by the Wnt/-catenin signaling pathway, which secretes Wnt ligands and activates Frizzled receptors on tumor cells, and the -catenin signaling pathway. -catenin translocates to the nucleus, prompting the expression of factors that promote tumorigenesis, such as cyclin D1 and myc proto-oncogene protein (c-Myc). These factors drive the proliferation and growth of pancreatic cancer cells.
#20 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
RAS signaling appears to play a critical role in both pancreatic cancer initiation and maintenance. […] Pancreatic cancers without KRAS mutations show RAS activation via upstream signaling through receptor tyrosine kinases (RTKs), e.g., epidermal growth factor receptor (EGFR), and oncogenic activation of the downstream B-Raf proto-oncogene (B-RAF) molecule is detected in a small number of patients. […] The WNT signaling pathway includes the canonical and noncanonical pathways and controls the maintenance of somatic stem cells in many tissues. […] Both the canonical (-catenin-dependent) and noncanonical (-catenin-independent) pathways have been implicated in pancreatic carcinogenesis, tumor progression, and therapeutic resistance. […] Pancreatic cancer is generally considered an extremely aggressive tumor with high metastatic propensity.
#21 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. […] In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. […] PDAC arises from noninvasive precancerous lesions that are curable if detected and treated early enough. […] Most PDACs arise from microscopic pancreatic intraepithelial neoplasia (PanIN), a neoplasm involving pancreatic ducts, which is by definition 5 mm. […] The unique pathological features of each lesion lead to distinct clinical challenges.
#22 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. […] In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. […] PDAC arises from noninvasive precancerous lesions that are curable if detected and treated early enough. […] Most PDACs arise from microscopic pancreatic intraepithelial neoplasia (PanIN), a neoplasm involving pancreatic ducts, which is by definition 5 mm. […] The unique pathological features of each lesion lead to distinct clinical challenges.
#23 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Development and progression of PC is a multistep process. Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma. […] Numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1â3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs. […] The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. […] Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth.
#24 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Development and progression of PC is a multistep process. Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma. […] Numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1â3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs. […] The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. […] Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth.
#25 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Development and progression of PC is a multistep process. Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma. […] Numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1â3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs. […] The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. […] Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth.
#26 The molecular pathogenesis of pancreatic cancer: clarifying a complex circuitry
https://genesdev.cshlp.org/content/20/22/3049.full.html
Through meticulous attention to morphology and nomenclature, it is now well established that PDAC has precursor lesions, termed PanIN for pancreatic intraepithelial neoplasia (Hruban et al. 2001). […] In the context of progression to PDAC, however, each PanIN stage is associated with increasingly frequent modifications in canonical oncogenes and tumor suppressor genes, such as Ki-RAS (90%100%), p16INK4a (90%95%), p53 (50%85%), DPC4/SMAD4 (50%), and BRCA2 (10%) (Hruban et al. 2000; Hezel et al. 2006). […] Understanding the biological differences between the PDAC from PanIN lesions and the invasive carcinomas that arise from IPMN and MCN lesions may not only unravel important molecular insights with therapeutic implications for all three classes of invasive disease. […] The major breakthrough emerged from an approach involving the targeted endogenous expression of activated KrasG12D in presumed progenitor cells, using either p48-Cre or Pdx1-Cre (Hingorani et al. 2003).
#27 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Development and progression of PC is a multistep process. Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma. […] Numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1â3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs. […] The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. […] Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth.
#28 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
PDACs exhibit multiple alterations to immune cell subtypes, resulting in an immunosuppressive or cold microenvironment. […] These alterations include increased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, preventing immune-mediated targeting of cancer cells. […] PDACs have a dense desmoplastic stroma that is produced by cancer-associated fibroblasts (CAFs). […] PDAC is characterized by extensive molecular alterations, including somatic mutations, chromosomal alterations, epigenetic modifications, and transcriptional reprogramming, all occurring in tumor cells.
#29 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
In PC, excessive desmoplastic reaction induces the proliferation of fibroblast cells and the production of extracellular matrix (ECM). […] Extracellular matrix forms fibrous mesh around tumor cells, and it has recently been shown that hyaluronan (HA), a major component of ECM, provides favorable microenvironment for PC progression by promoting malignant cell proliferation, aggressiveness and resistance to cancer therapy, resulting in poor prognosis. […] It is thus clear that PC pathogenesis involves a complex interplay of multiple factors. In addition to the different interactions of tumor cells with their immediate surroundings, several molecular alterations are responsible for PC onset and progression. […] Several molecular events are now believed responsible for the progression of PC. These include genetic, as well as epigenetic changes. Genetic events include mutations in key genes, activation of oncogenes and inactivation of tumor suppressors. In addition, epigenetic regulation through non-coding RNAs is also increasingly being recognized in PC initiation, as well as progression.
#30 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
In PC, excessive desmoplastic reaction induces the proliferation of fibroblast cells and the production of extracellular matrix (ECM). […] Extracellular matrix forms fibrous mesh around tumor cells, and it has recently been shown that hyaluronan (HA), a major component of ECM, provides favorable microenvironment for PC progression by promoting malignant cell proliferation, aggressiveness and resistance to cancer therapy, resulting in poor prognosis. […] It is thus clear that PC pathogenesis involves a complex interplay of multiple factors. In addition to the different interactions of tumor cells with their immediate surroundings, several molecular alterations are responsible for PC onset and progression. […] Several molecular events are now believed responsible for the progression of PC. These include genetic, as well as epigenetic changes. Genetic events include mutations in key genes, activation of oncogenes and inactivation of tumor suppressors. In addition, epigenetic regulation through non-coding RNAs is also increasingly being recognized in PC initiation, as well as progression.
#31 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
PDACs exhibit multiple alterations to immune cell subtypes, resulting in an immunosuppressive or cold microenvironment. […] These alterations include increased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, preventing immune-mediated targeting of cancer cells. […] PDACs have a dense desmoplastic stroma that is produced by cancer-associated fibroblasts (CAFs). […] PDAC is characterized by extensive molecular alterations, including somatic mutations, chromosomal alterations, epigenetic modifications, and transcriptional reprogramming, all occurring in tumor cells.
#32 Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC9516440/
PDACs exhibit multiple alterations to immune cell subtypes, resulting in an immunosuppressive or cold microenvironment. […] These alterations include increased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, preventing immune-mediated targeting of cancer cells. […] PDACs have a dense desmoplastic stroma that is produced by cancer-associated fibroblasts (CAFs). […] PDAC is characterized by extensive molecular alterations, including somatic mutations, chromosomal alterations, epigenetic modifications, and transcriptional reprogramming, all occurring in tumor cells.
#33 Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward
https://www.mdpi.com/1422-0067/18/4/779
Development and progression of PC is a multistep process. Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma. […] Numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1â3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs. […] The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. […] Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth.
#34 Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways
https://www.wjgnet.com/2218-4333/full/v16/i2/97007.htm
The TGF- signaling pathway also plays a crucial role in modulating the efficacy of chemotherapeutic drugs for pancreatic cancer. An in-depth study of the complex role of TGF- signaling in pancreatic cancer development is essential for the advancement of targeted treatment approaches. […] The Hh signaling pathway is crucial for pancreatic cancer development through various mechanisms, including the activation of CAFs, the regulation of tumor cell survival and growth, and the TME. These studies help elucidate the pathophysiology of pancreatic cancer and provide a scientific basis for developing anticancer strategies targeting the Hh pathway. […] The interaction between CAFs and pancreatic cancer cells is significantly influenced by the Wnt/-catenin signaling pathway, which secretes Wnt ligands and activates Frizzled receptors on tumor cells, and the -catenin signaling pathway. -catenin translocates to the nucleus, prompting the expression of factors that promote tumorigenesis, such as cyclin D1 and myc proto-oncogene protein (c-Myc). These factors drive the proliferation and growth of pancreatic cancer cells.
#35 Molecular mechanism of pancreatic ductal adenocarcinoma: The heterogeneity of cancer-associated fibroblasts and key signaling pathways
https://www.wjgnet.com/2218-4333/full/v16/i2/97007.htm
Cytokines secreted by CAFs, such as IL-6 and IL-11, activate receptors located on the tumor cell surface, promoting the JAK/STAT signaling pathway. This activation supports tumor cell survival, proliferation, and invasion. Understanding the molecular characteristics of CAFs and their role in the TME is essential for formulating effective treatment strategies. […] In summary, this study establishes a novel scientific basis for treating pancreatic cancer, highlighting the importance of deep signaling pathway research in the formulation of effective therapeutic strategies. This approach has the potential to achieve breakthroughs in precision medicine and targeted therapy.
#36 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
It has been demonstrated that metastasis can occur during the early stages of pancreatic cancer, even before large mass formation by the primary tumor. […] The pancreatic tumor microenvironment is indispensable for pancreatic cancer progression. […] The tumor microenvironment in pancreatic cancer is highly immunosuppressive and is characterized by an abundant stromal response as a desmoplastic reaction. […] The crosstalk between tumor cells and the stromal microenvironment is complex, and stromal elements regulate pancreatic cancer progression in a more complex manner. […] The high prevalence of KRAS mutations (carried by 90% of pancreatic cancer patients) has led to considerable interest in KRAS-targeted therapies. […] A deeper understanding of the biology and genetics of pancreatic cancer, including new insight into driver gene mutations, tumor metabolism, and the tumor microenvironment, might lead to promising and innovative therapeutic strategies.
#37 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
It has been demonstrated that metastasis can occur during the early stages of pancreatic cancer, even before large mass formation by the primary tumor. […] The pancreatic tumor microenvironment is indispensable for pancreatic cancer progression. […] The tumor microenvironment in pancreatic cancer is highly immunosuppressive and is characterized by an abundant stromal response as a desmoplastic reaction. […] The crosstalk between tumor cells and the stromal microenvironment is complex, and stromal elements regulate pancreatic cancer progression in a more complex manner. […] The high prevalence of KRAS mutations (carried by 90% of pancreatic cancer patients) has led to considerable interest in KRAS-targeted therapies. […] A deeper understanding of the biology and genetics of pancreatic cancer, including new insight into driver gene mutations, tumor metabolism, and the tumor microenvironment, might lead to promising and innovative therapeutic strategies.
#38 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. […] Importantly, metabolic changes at the body level deserve more attention. […] A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches. […] Metabolic reprogramming, which refers to the adaptive changes in the balance of anabolism and catabolism that occur in tumour cells during the malignant development process to meet the large demand for materials and energy, has gradually become recognized as one of the crucial hallmarks of cancer. […] Exploring the metabolic regulatory network and underlying mechanisms, formulating comprehensive treatment strategies, and promoting precise treatment based on individual patients are expected to improve the overall prognosis.
#39 Newfound Mechanism Suggests Drug Combination Could Starve Pancreatic Cancer | NYU Langone News
https://nyulangone.org/news/newfound-mechanism-suggests-drug-combination-could-starve-pancreatic-cancer
A new combination of treatments safely decreased growth of pancreatic cancer in mice by preventing cancer cells from scavenging for fuel, a new study finds. […] The work builds on prior discoveries at NYU Langone Health that revealed how pancreatic cancer cells, to avert starvation and keep growing, find alternate fuel sources. […] In this environment, the ability to switch fuels contributes to the deadliness of pancreatic cancers. […] Published online October 9 in Nature Cancer, the new study involves a drug designed to prevent pancreatic ductal adenocarcinoma (PDAC) cells from one such switch. […] PDAC cells use the enzyme glutaminase to convert the amino acid glutamate into glutamine, which can be burned for fuel to sustain rapid tumor growth. […] Drugs designed to block glutaminase, however, have been shown to cause cancer cells to switch to still other scavenging pathways.
#40 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
In addition, many studies have found that other amino acids, such as serine, tryptophan, methionine, and branched-chain amino acids (BCAAs) such as leucine, play a role in different stages of tumors and are expected to develop new intervention strategies. […] The regulation of de novo lipogenesis mainly occurs at the transcription level, and sterol regulatory element binding proteins (SREBPs) can regulate genes related to fatty acid and cholesterol synthesis and uptake. […] Cholesterol plays a key role in maintaining membrane integrity and fluidity and regulating cell signalling events. […] Abnormal cholesterol metabolism can support PDAC growth. […] Targeting SOAT1 can affect p53 mutant PDAC organoids that are sensitive to cholesterol metabolism and impair tumor progression. […] Fatty acid oxidation (FAO), also known as -oxidation, is increased in many cancer cells because cancer cells can use fatty acid (FA) catabolism to proliferate when ATP is depleted. […] FAO can participate in tumorigenesis and tumour metastasis and may be related to cachexia.
#41 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
In addition, many studies have found that other amino acids, such as serine, tryptophan, methionine, and branched-chain amino acids (BCAAs) such as leucine, play a role in different stages of tumors and are expected to develop new intervention strategies. […] The regulation of de novo lipogenesis mainly occurs at the transcription level, and sterol regulatory element binding proteins (SREBPs) can regulate genes related to fatty acid and cholesterol synthesis and uptake. […] Cholesterol plays a key role in maintaining membrane integrity and fluidity and regulating cell signalling events. […] Abnormal cholesterol metabolism can support PDAC growth. […] Targeting SOAT1 can affect p53 mutant PDAC organoids that are sensitive to cholesterol metabolism and impair tumor progression. […] Fatty acid oxidation (FAO), also known as -oxidation, is increased in many cancer cells because cancer cells can use fatty acid (FA) catabolism to proliferate when ATP is depleted. […] FAO can participate in tumorigenesis and tumour metastasis and may be related to cachexia.
#42 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
In addition, many studies have found that other amino acids, such as serine, tryptophan, methionine, and branched-chain amino acids (BCAAs) such as leucine, play a role in different stages of tumors and are expected to develop new intervention strategies. […] The regulation of de novo lipogenesis mainly occurs at the transcription level, and sterol regulatory element binding proteins (SREBPs) can regulate genes related to fatty acid and cholesterol synthesis and uptake. […] Cholesterol plays a key role in maintaining membrane integrity and fluidity and regulating cell signalling events. […] Abnormal cholesterol metabolism can support PDAC growth. […] Targeting SOAT1 can affect p53 mutant PDAC organoids that are sensitive to cholesterol metabolism and impair tumor progression. […] Fatty acid oxidation (FAO), also known as -oxidation, is increased in many cancer cells because cancer cells can use fatty acid (FA) catabolism to proliferate when ATP is depleted. […] FAO can participate in tumorigenesis and tumour metastasis and may be related to cachexia.
#43 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Cellular redox homeostasis is an important process for cell survival, and ROS can cause damage to cellular components. […] Several transcription factors are activated by ROS, regulate the redox status of cells and are implicated in carcinogenesis. […] KRAS mutations are among the earliest events in pancreatic carcinogenesis and can drive common metabolic programs and promote tumour progression. […] In the transformed state, KRAS PDAC cells possess metabolic programs intrinsic to acinar and ductal cells. […] To adapt to harsh environments, PDAC cells rely on lysosomes for nutrient degradation and regeneration, such as through macropinocytosis and autophagy, to obtain sufficient fuel for survival. […] Research has shown that autophagy promotes immune evasion in PDAC by degrading MHC-I and that the combination of MEK and autophagy inhibition may inhibit PDAC.
#44 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Cellular redox homeostasis is an important process for cell survival, and ROS can cause damage to cellular components. […] Several transcription factors are activated by ROS, regulate the redox status of cells and are implicated in carcinogenesis. […] KRAS mutations are among the earliest events in pancreatic carcinogenesis and can drive common metabolic programs and promote tumour progression. […] In the transformed state, KRAS PDAC cells possess metabolic programs intrinsic to acinar and ductal cells. […] To adapt to harsh environments, PDAC cells rely on lysosomes for nutrient degradation and regeneration, such as through macropinocytosis and autophagy, to obtain sufficient fuel for survival. […] Research has shown that autophagy promotes immune evasion in PDAC by degrading MHC-I and that the combination of MEK and autophagy inhibition may inhibit PDAC.
#45 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
RAS signaling appears to play a critical role in both pancreatic cancer initiation and maintenance. […] Pancreatic cancers without KRAS mutations show RAS activation via upstream signaling through receptor tyrosine kinases (RTKs), e.g., epidermal growth factor receptor (EGFR), and oncogenic activation of the downstream B-Raf proto-oncogene (B-RAF) molecule is detected in a small number of patients. […] The WNT signaling pathway includes the canonical and noncanonical pathways and controls the maintenance of somatic stem cells in many tissues. […] Both the canonical (-catenin-dependent) and noncanonical (-catenin-independent) pathways have been implicated in pancreatic carcinogenesis, tumor progression, and therapeutic resistance. […] Pancreatic cancer is generally considered an extremely aggressive tumor with high metastatic propensity.
#46 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
It has been demonstrated that metastasis can occur during the early stages of pancreatic cancer, even before large mass formation by the primary tumor. […] The pancreatic tumor microenvironment is indispensable for pancreatic cancer progression. […] The tumor microenvironment in pancreatic cancer is highly immunosuppressive and is characterized by an abundant stromal response as a desmoplastic reaction. […] The crosstalk between tumor cells and the stromal microenvironment is complex, and stromal elements regulate pancreatic cancer progression in a more complex manner. […] The high prevalence of KRAS mutations (carried by 90% of pancreatic cancer patients) has led to considerable interest in KRAS-targeted therapies. […] A deeper understanding of the biology and genetics of pancreatic cancer, including new insight into driver gene mutations, tumor metabolism, and the tumor microenvironment, might lead to promising and innovative therapeutic strategies.
#47 Long-sought mechanism of metastasis is discovered in pancreatic cancer | Cold Spring Harbor Laboratory
https://www.cshl.edu/long-sought-mechanism-metastasis-discovered-pancreatic-cancer/
Cells that become cancerous may be making use of molecular memories imprinted during their earliest days to power their ability to metastasize, or spread to distant sites in the body. […] The research, appearing online today in Cell, provides strong evidence supporting this explanation of metastasis, which is the cause of most cancer deaths. It pertains specifically to cells involved in the most common form of pancreatic cancer, called pancreatic ductal adenocarcinoma or PDA. […] Experiments revealed that cancer cells became capable of metastasis via an epigenetic reprogramming of gene enhancers, reverting them to an earlier developmental state characterized by proliferation and increased mobility. […] The Vakoc team’s new results make a case for metastasis to have epigenetic roots. […] Formation of a tumor is driven by genetic events but its ability to spread may not involve direct changes in the DNA sequence, says Dr. Roe.
#48 Long-sought mechanism of metastasis is discovered in pancreatic cancer | Cold Spring Harbor Laboratory
https://www.cshl.edu/long-sought-mechanism-metastasis-discovered-pancreatic-cancer/
Cells that become cancerous may be making use of molecular memories imprinted during their earliest days to power their ability to metastasize, or spread to distant sites in the body. […] The research, appearing online today in Cell, provides strong evidence supporting this explanation of metastasis, which is the cause of most cancer deaths. It pertains specifically to cells involved in the most common form of pancreatic cancer, called pancreatic ductal adenocarcinoma or PDA. […] Experiments revealed that cancer cells became capable of metastasis via an epigenetic reprogramming of gene enhancers, reverting them to an earlier developmental state characterized by proliferation and increased mobility. […] The Vakoc team’s new results make a case for metastasis to have epigenetic roots. […] Formation of a tumor is driven by genetic events but its ability to spread may not involve direct changes in the DNA sequence, says Dr. Roe.
#49 Long-sought mechanism of metastasis is discovered in pancreatic cancer | Cold Spring Harbor Laboratory
https://www.cshl.edu/long-sought-mechanism-metastasis-discovered-pancreatic-cancer/
Cells that become cancerous may be making use of molecular memories imprinted during their earliest days to power their ability to metastasize, or spread to distant sites in the body. […] The research, appearing online today in Cell, provides strong evidence supporting this explanation of metastasis, which is the cause of most cancer deaths. It pertains specifically to cells involved in the most common form of pancreatic cancer, called pancreatic ductal adenocarcinoma or PDA. […] Experiments revealed that cancer cells became capable of metastasis via an epigenetic reprogramming of gene enhancers, reverting them to an earlier developmental state characterized by proliferation and increased mobility. […] The Vakoc team’s new results make a case for metastasis to have epigenetic roots. […] Formation of a tumor is driven by genetic events but its ability to spread may not involve direct changes in the DNA sequence, says Dr. Roe.
#50 Long-sought mechanism of metastasis is discovered in pancreatic cancer | Cold Spring Harbor Laboratory
https://www.cshl.edu/long-sought-mechanism-metastasis-discovered-pancreatic-cancer/
Compared with cells in non-cancerous and tumor-derived organoids, those in metastatic ones displayed an extraordinary number of alterations in regions called enhancers. […] FOXA1 activation, inducing enhancer reprogramming that endows a cancer cell with metastatic properties, is an epigenetic mechanism, as opposed to a genetic one, that explains at least one mechanism of metastasis in this form of pancreatic cancer, and likely, other cancer types as well. […] It seems quite plausible from our results that reprogramming of enhancers enables cancer cells, generally, to achieve metastatic competence.
#51 Long-sought mechanism of metastasis is discovered in pancreatic cancer | Cold Spring Harbor Laboratory
https://www.cshl.edu/long-sought-mechanism-metastasis-discovered-pancreatic-cancer/
Compared with cells in non-cancerous and tumor-derived organoids, those in metastatic ones displayed an extraordinary number of alterations in regions called enhancers. […] FOXA1 activation, inducing enhancer reprogramming that endows a cancer cell with metastatic properties, is an epigenetic mechanism, as opposed to a genetic one, that explains at least one mechanism of metastasis in this form of pancreatic cancer, and likely, other cancer types as well. […] It seems quite plausible from our results that reprogramming of enhancers enables cancer cells, generally, to achieve metastatic competence.
#52 Pathogenesis and Treatment of Pancreatic Cancer Related Pain | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1789
Pancreatic cancer is often diagnosed due to the patient seeking medical attention for abdominal pain. Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis resulting in neuropathic pain. […] Pain management is especially challenging, due to advanced patient age, the aggressive nature of the disease and the use of aggressive treatment regimen. Interestingly, the presence and severity of pain in pancreatic cancer patients correlates strongly with pancreatic cancer prognosis and an adverse tumor microenvironment, suggesting that a more toxic cancer environment correlates with increased nerve damage. […] Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis. Extra-pancreatic nerve plexus invasion is responsible for the neuropathic pain sensation.
#53 Pathogenesis and Treatment of Pancreatic Cancer Related Pain | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1789
Pancreatic cancer is often diagnosed due to the patient seeking medical attention for abdominal pain. Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis resulting in neuropathic pain. […] Pain management is especially challenging, due to advanced patient age, the aggressive nature of the disease and the use of aggressive treatment regimen. Interestingly, the presence and severity of pain in pancreatic cancer patients correlates strongly with pancreatic cancer prognosis and an adverse tumor microenvironment, suggesting that a more toxic cancer environment correlates with increased nerve damage. […] Perineural invasion is a prominent feature of pancreatic cancer and often the first route of metastasis. Extra-pancreatic nerve plexus invasion is responsible for the neuropathic pain sensation.
#54 Pathogenesis and Treatment of Pancreatic Cancer Related Pain | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1789
Similarities in growth factor receptors and adhesion molecules between pancreatic cancer cells and neuronal cells, explain the affinity to neural tissue and lead to increased cancer cell proliferation, and migration and invasion along nerve bundles. Pancreatic cancer cell migration along nerve bundles results in neuropathic pain, increased neuroplasticity and pain sensation in response to growth stimulation of sensory fibers. […] Epigenetic changes may contribute to the development of several pain symptoms and the manifestation of chronic pain. In addition to providing a valuable insight into the molecular mechanisms of pain development and chronic pain syndromes, some studies have provided evidence regarding the use of epigenetic modulation as a potential therapeutic option for cancer-related pain.
#55 Pathogenesis and Treatment of Pancreatic Cancer Related Pain | Anticancer Research
https://ar.iiarjournals.org/content/40/4/1789
Similarities in growth factor receptors and adhesion molecules between pancreatic cancer cells and neuronal cells, explain the affinity to neural tissue and lead to increased cancer cell proliferation, and migration and invasion along nerve bundles. Pancreatic cancer cell migration along nerve bundles results in neuropathic pain, increased neuroplasticity and pain sensation in response to growth stimulation of sensory fibers. […] Epigenetic changes may contribute to the development of several pain symptoms and the manifestation of chronic pain. In addition to providing a valuable insight into the molecular mechanisms of pain development and chronic pain syndromes, some studies have provided evidence regarding the use of epigenetic modulation as a potential therapeutic option for cancer-related pain.
#56
https://journals.lww.com/jpancreatology/fulltext/2023/12000/pancreatic_cancer_related_pain__mechanism_and.8.aspx
The molecular mechanism of PNI is complicated, mainly involves neurotrophins and their receptors (eg, nerve growth factor [NGF]), proteinases (metalloproteinases [MMP]), cytokines (eg, transforming growth factor [TGF], epidermal growth factor [EGFR]), chemokines (eg, CX3CL1, CX3CR1), and cell-surface markers (eg, MUC1, NCAM). […] Increased NGF/TrkA expression levels in PC was found to be associated with more severe pain. […] A recent research found that sonic hedgehog (sHH) signaling pathway could influence NGF signaling pathway, and increase the expression of substance P (SP) and CGRP in dorsal root ganglions in an NGF-dependent manner. […] Neovascularization in PC is associated with the sensitization and activation of nociceptors through cross-talking between them. […] Increased neural density and hypertrophy were detected in PC patients, consistent with their abdominal pain and severity of pancreatic neuritis.
#57 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
Chemoresistance is a critical issue in pancreatic cancer. Among mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways, the influence exerted by tumor microenvironment (desmoplastic reaction) and the presence of highly resistant cancer stem cells (CSCs). […] Cancer stem cells, identified in a large number of human malignancies, represent 0.2%-0.8% of pancreatic cancer cells and are considered responsible for tumor growth, invasion, metastasis and recurrence. […] Several studies argue that cancer stem cells cannot be eradicated by current therapy and thus are responsible for tumor relapse and metastasis. […] Many studies have demonstrated that multiple critical genes, including K-ras, p53 and p16, and key signaling kinases, such as PI-3K, mTOR, NF-B, epidermal growth factor receptor (EGFR) and SHH, play important roles in pancreatic tumorigenesis.
#58 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
Chemoresistance is a critical issue in pancreatic cancer. Among mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways, the influence exerted by tumor microenvironment (desmoplastic reaction) and the presence of highly resistant cancer stem cells (CSCs). […] Cancer stem cells, identified in a large number of human malignancies, represent 0.2%-0.8% of pancreatic cancer cells and are considered responsible for tumor growth, invasion, metastasis and recurrence. […] Several studies argue that cancer stem cells cannot be eradicated by current therapy and thus are responsible for tumor relapse and metastasis. […] Many studies have demonstrated that multiple critical genes, including K-ras, p53 and p16, and key signaling kinases, such as PI-3K, mTOR, NF-B, epidermal growth factor receptor (EGFR) and SHH, play important roles in pancreatic tumorigenesis.
#59 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
The high mortality rate of pancreatic cancer is due to difficulty in early diagnosis and its notorious resistance to chemotherapy and radiation. […] The notion of CSCs has gained prominence, and several identified molecules and signaling pathways are relevant for the diagnosis and therapy of cancer. […] The presence of cancer stem cells was reported in 2007 by Shah et al who showed that CD44+CD24+ESA+ cells exhibit high tumorigenic potential. […] The resistance of CSCs has been explained by several mechanisms: (1) expression of multidrug resistance-linked genes, largely ATP-binding cassette (ABC) drug transporters; (2) activation of Wnt/Î²-catenin signaling; and (3) activation of Hedgehog pathway. […] The emergence of cancer stem cells is based on genetic alterations and modifications in signaling pathways that result in the transformation of normal stem cells, progenitors or differentiated cells.
#60 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
The high mortality rate of pancreatic cancer is due to difficulty in early diagnosis and its notorious resistance to chemotherapy and radiation. […] The notion of CSCs has gained prominence, and several identified molecules and signaling pathways are relevant for the diagnosis and therapy of cancer. […] The presence of cancer stem cells was reported in 2007 by Shah et al who showed that CD44+CD24+ESA+ cells exhibit high tumorigenic potential. […] The resistance of CSCs has been explained by several mechanisms: (1) expression of multidrug resistance-linked genes, largely ATP-binding cassette (ABC) drug transporters; (2) activation of Wnt/Î²-catenin signaling; and (3) activation of Hedgehog pathway. […] The emergence of cancer stem cells is based on genetic alterations and modifications in signaling pathways that result in the transformation of normal stem cells, progenitors or differentiated cells.
#61 Pancreatic Cancer: Updates in Pathogenesis and Therapies | IntechOpen
https://www.intechopen.com/chapters/88046
The developmental shift of PDAC cells from the epithelial to the mesenchymal or fibroblastoid phenotype epithelial mesenchymal transmission (EMT) is considered a vital step in the progression of the primary tumours to the invasive/metastatic/drug-resistant ones. […] Due to their self-renewing and differentiation capabilities, PCSCs have a role in PC initiating and progression through tumour growth, invasion, metastasis, recurrence, and chemo/radio-resistance. […] The microbiota imbalance (dysbiosis), and their combined genetic material (microbiome), have a major role in initiation and progression of tumours like PDAC by gene mutation, changing the TME immunity, altering tumour metabolism, promoting tumour inflammatory responses, and by promoting drug resistance.
#62 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
The high mortality rate of pancreatic cancer is due to difficulty in early diagnosis and its notorious resistance to chemotherapy and radiation. […] The notion of CSCs has gained prominence, and several identified molecules and signaling pathways are relevant for the diagnosis and therapy of cancer. […] The presence of cancer stem cells was reported in 2007 by Shah et al who showed that CD44+CD24+ESA+ cells exhibit high tumorigenic potential. […] The resistance of CSCs has been explained by several mechanisms: (1) expression of multidrug resistance-linked genes, largely ATP-binding cassette (ABC) drug transporters; (2) activation of Wnt/Î²-catenin signaling; and (3) activation of Hedgehog pathway. […] The emergence of cancer stem cells is based on genetic alterations and modifications in signaling pathways that result in the transformation of normal stem cells, progenitors or differentiated cells.
#63 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
Sequencing data have revealed that pancreatic cancer comprises highly heterogeneous tumors that develop resistance to traditional chemotherapy and radiation therapy. […] It is evident that KRAS mutation seems to be necessary but not sufficient for pancreatic cancer development. […] Other genes, including tumor protein p53 (TP53), cyclin-dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4), are also frequently involved in pancreatic cancer tumorigenesis and metastasis. […] In pancreatic cancer, the frequent loss of SMAD4 via homozygous deletion or mutation leads to decreasing SMAD4-dependent inhibition of transforming growth factor- (TGF-) and the promotion of noncanonical TGF- signaling, thereby facilitating pro-tumorigenic responses. […] Signaling pathways (e.g., RAS, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B), janus kinase (JAK)/signal transducer and activator of transcription (STAT), Hippo/yes-kinase-associated-protein (YAP), Wingless/int1 (WNT), etc.) have been linked to a variety of cancer-related cellular processes, including cell proliferation, differentiation, apoptosis, migration, angiogenesis, metabolism, and immune regulation.
#64 Cancer stem cells: Involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics
https://www.wjgnet.com/1007-9327/full/v20/i31/10790.htm
Chemoresistance is a critical issue in pancreatic cancer. Among mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways, the influence exerted by tumor microenvironment (desmoplastic reaction) and the presence of highly resistant cancer stem cells (CSCs). […] Cancer stem cells, identified in a large number of human malignancies, represent 0.2%-0.8% of pancreatic cancer cells and are considered responsible for tumor growth, invasion, metastasis and recurrence. […] Several studies argue that cancer stem cells cannot be eradicated by current therapy and thus are responsible for tumor relapse and metastasis. […] Many studies have demonstrated that multiple critical genes, including K-ras, p53 and p16, and key signaling kinases, such as PI-3K, mTOR, NF-B, epidermal growth factor receptor (EGFR) and SHH, play important roles in pancreatic tumorigenesis.
#65 Uncovering the Mechanism for Drug Resistance in Pancreatic Cancer | University of Virginia School of Engineering and Applied Science
https://engineering.virginia.edu/news-events/news/uncovering-mechanism-drug-resistance-pancreatic-cancer
Researchers at the University of Virginia have discovered a new mechanism driving drug resistance in pancreatic ductal adenocarcinoma, one of the deadliest cancers. […] Pancreatic tumors are notorious for their resistance to chemotherapy, due in part to their dense, poorly vascularized tissue structure, which creates areas of low oxygen, or hypoxia, within the tumor. […] The teams findings were striking. They showed that hypoxia indeed pushes pancreatic cancer cells into a more aggressive, chemoresistant state. […] The study, published in Cancer Research, revealed that when pancreatic cancer cells are deprived of oxygen, a specific process is activated inside the cells. This process involves changes in the way the cells genetic material is modified and how signals are sent within the cell, making the cancer cells stronger and more resistant to chemotherapy.
#66 Uncovering the Mechanism for Drug Resistance in Pancreatic Cancer | University of Virginia School of Engineering and Applied Science
https://engineering.virginia.edu/news-events/news/uncovering-mechanism-drug-resistance-pancreatic-cancer
Researchers at the University of Virginia have discovered a new mechanism driving drug resistance in pancreatic ductal adenocarcinoma, one of the deadliest cancers. […] Pancreatic tumors are notorious for their resistance to chemotherapy, due in part to their dense, poorly vascularized tissue structure, which creates areas of low oxygen, or hypoxia, within the tumor. […] The teams findings were striking. They showed that hypoxia indeed pushes pancreatic cancer cells into a more aggressive, chemoresistant state. […] The study, published in Cancer Research, revealed that when pancreatic cancer cells are deprived of oxygen, a specific process is activated inside the cells. This process involves changes in the way the cells genetic material is modified and how signals are sent within the cell, making the cancer cells stronger and more resistant to chemotherapy.
#67 Uncovering the Mechanism for Drug Resistance in Pancreatic Cancer | University of Virginia School of Engineering and Applied Science
https://engineering.virginia.edu/news-events/news/uncovering-mechanism-drug-resistance-pancreatic-cancer
Researchers at the University of Virginia have discovered a new mechanism driving drug resistance in pancreatic ductal adenocarcinoma, one of the deadliest cancers. […] Pancreatic tumors are notorious for their resistance to chemotherapy, due in part to their dense, poorly vascularized tissue structure, which creates areas of low oxygen, or hypoxia, within the tumor. […] The teams findings were striking. They showed that hypoxia indeed pushes pancreatic cancer cells into a more aggressive, chemoresistant state. […] The study, published in Cancer Research, revealed that when pancreatic cancer cells are deprived of oxygen, a specific process is activated inside the cells. This process involves changes in the way the cells genetic material is modified and how signals are sent within the cell, making the cancer cells stronger and more resistant to chemotherapy.
#68 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
Autophagy, a lysosomal-mediated, highly conserved degradation process that removes abnormal proteins and damaged organelles from the body, is upregulated in pancreatic ductal adenocarcinoma. […] In the initial phase, autophagy inhibits the transformation of precancerous lesions to cancer. However, in the progressive stage, autophagy promotes tumor growth. Autophagy is also one of the main mechanisms of drug resistance during treatment. […] Autophagy regulates inflammation during PDAC pathogenesis. Studies have shown that knockout of autophagy-related genes (ATG5 or ATG7) or proteins encoding lysosomal function LAMP2 leads to severe acinar cell degeneration, pancreatic atrophy, fibrosis, and inflammation. […] This indicates that autophagy inhibition increases a patients susceptibility to PDAC.
#69 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
Autophagy, a lysosomal-mediated, highly conserved degradation process that removes abnormal proteins and damaged organelles from the body, is upregulated in pancreatic ductal adenocarcinoma. […] In the initial phase, autophagy inhibits the transformation of precancerous lesions to cancer. However, in the progressive stage, autophagy promotes tumor growth. Autophagy is also one of the main mechanisms of drug resistance during treatment. […] Autophagy regulates inflammation during PDAC pathogenesis. Studies have shown that knockout of autophagy-related genes (ATG5 or ATG7) or proteins encoding lysosomal function LAMP2 leads to severe acinar cell degeneration, pancreatic atrophy, fibrosis, and inflammation. […] This indicates that autophagy inhibition increases a patients susceptibility to PDAC.
#70 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
Autophagy, a lysosomal-mediated, highly conserved degradation process that removes abnormal proteins and damaged organelles from the body, is upregulated in pancreatic ductal adenocarcinoma. […] In the initial phase, autophagy inhibits the transformation of precancerous lesions to cancer. However, in the progressive stage, autophagy promotes tumor growth. Autophagy is also one of the main mechanisms of drug resistance during treatment. […] Autophagy regulates inflammation during PDAC pathogenesis. Studies have shown that knockout of autophagy-related genes (ATG5 or ATG7) or proteins encoding lysosomal function LAMP2 leads to severe acinar cell degeneration, pancreatic atrophy, fibrosis, and inflammation. […] This indicates that autophagy inhibition increases a patients susceptibility to PDAC.
#71 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
Autophagy can inhibit PDAC pathogenesis, but can provide energy for cells, promoting PDAC onset when pancreatic cells have carcinogenic KRAS mutations. […] The different results may be related to Rosenfeldts use of the P53 homozygous deletion model. […] In human PDAC cells, there is typically only one deletion of the P53 allele. […] Thus, according to the above studies, manipulating autophagy to treat PDAC may depend on the KRAS oncogene status. […] PDAC cells feature increased mitochondrial destruction compared with normal cells. […] It is essential for cell homeostasis to maintain healthy mitochondria, including quantity and quality. […] Therefore, mitochondrial autophagy is increased in PDAC cells and it selectively degrades damaged mitochondria. […] However, the role of autophagy in PDAC remains to be further elucidated.
#72 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
Autophagy can inhibit PDAC pathogenesis, but can provide energy for cells, promoting PDAC onset when pancreatic cells have carcinogenic KRAS mutations. […] The different results may be related to Rosenfeldts use of the P53 homozygous deletion model. […] In human PDAC cells, there is typically only one deletion of the P53 allele. […] Thus, according to the above studies, manipulating autophagy to treat PDAC may depend on the KRAS oncogene status. […] PDAC cells feature increased mitochondrial destruction compared with normal cells. […] It is essential for cell homeostasis to maintain healthy mitochondria, including quantity and quality. […] Therefore, mitochondrial autophagy is increased in PDAC cells and it selectively degrades damaged mitochondria. […] However, the role of autophagy in PDAC remains to be further elucidated.
#73 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
It has been demonstrated that metastasis can occur during the early stages of pancreatic cancer, even before large mass formation by the primary tumor. […] The pancreatic tumor microenvironment is indispensable for pancreatic cancer progression. […] The tumor microenvironment in pancreatic cancer is highly immunosuppressive and is characterized by an abundant stromal response as a desmoplastic reaction. […] The crosstalk between tumor cells and the stromal microenvironment is complex, and stromal elements regulate pancreatic cancer progression in a more complex manner. […] The high prevalence of KRAS mutations (carried by 90% of pancreatic cancer patients) has led to considerable interest in KRAS-targeted therapies. […] A deeper understanding of the biology and genetics of pancreatic cancer, including new insight into driver gene mutations, tumor metabolism, and the tumor microenvironment, might lead to promising and innovative therapeutic strategies.
#74 The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives | Signal Transduction and Targeted Therapy
https://www.nature.com/articles/s41392-021-00659-4
It has been demonstrated that metastasis can occur during the early stages of pancreatic cancer, even before large mass formation by the primary tumor. […] The pancreatic tumor microenvironment is indispensable for pancreatic cancer progression. […] The tumor microenvironment in pancreatic cancer is highly immunosuppressive and is characterized by an abundant stromal response as a desmoplastic reaction. […] The crosstalk between tumor cells and the stromal microenvironment is complex, and stromal elements regulate pancreatic cancer progression in a more complex manner. […] The high prevalence of KRAS mutations (carried by 90% of pancreatic cancer patients) has led to considerable interest in KRAS-targeted therapies. […] A deeper understanding of the biology and genetics of pancreatic cancer, including new insight into driver gene mutations, tumor metabolism, and the tumor microenvironment, might lead to promising and innovative therapeutic strategies.
#75 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Pancreatic cancer (PC), is an aggressive cancer with a poor prognosis. […] The overall five-year survival rate is less than 13%, and it is expected that PC will rank second in malignant tumour-related deaths in the United States by 2030. […] Targeting key enzymes in metabolic pathways can affect the progression of pancreatic cancer. […] The complex tumor microenvironment of pancreatic cancer creates metabolic heterogeneity. […] Clinical trials exploring metabolic-based treatments for pancreatic cancer have been initiated. […] Systemic metabolism can also serve as a potential pathogenic mechanism and therapeutic target. […] The adaptation of PDAC cells to nutrient deprivation is reversible, and glutamine synthetase (GS) is expected to become a therapeutic target for patients with PDAC.
#76 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Pancreatic cancer (PC), is an aggressive cancer with a poor prognosis. […] The overall five-year survival rate is less than 13%, and it is expected that PC will rank second in malignant tumour-related deaths in the United States by 2030. […] Targeting key enzymes in metabolic pathways can affect the progression of pancreatic cancer. […] The complex tumor microenvironment of pancreatic cancer creates metabolic heterogeneity. […] Clinical trials exploring metabolic-based treatments for pancreatic cancer have been initiated. […] Systemic metabolism can also serve as a potential pathogenic mechanism and therapeutic target. […] The adaptation of PDAC cells to nutrient deprivation is reversible, and glutamine synthetase (GS) is expected to become a therapeutic target for patients with PDAC.
#77 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
In addition, many studies have found that other amino acids, such as serine, tryptophan, methionine, and branched-chain amino acids (BCAAs) such as leucine, play a role in different stages of tumors and are expected to develop new intervention strategies. […] The regulation of de novo lipogenesis mainly occurs at the transcription level, and sterol regulatory element binding proteins (SREBPs) can regulate genes related to fatty acid and cholesterol synthesis and uptake. […] Cholesterol plays a key role in maintaining membrane integrity and fluidity and regulating cell signalling events. […] Abnormal cholesterol metabolism can support PDAC growth. […] Targeting SOAT1 can affect p53 mutant PDAC organoids that are sensitive to cholesterol metabolism and impair tumor progression. […] Fatty acid oxidation (FAO), also known as -oxidation, is increased in many cancer cells because cancer cells can use fatty acid (FA) catabolism to proliferate when ATP is depleted. […] FAO can participate in tumorigenesis and tumour metastasis and may be related to cachexia.
#78 PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications | Molecular Cancer | Full Text
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-020-01167-9
According to this principle, PARP inhibitors have received great attention. PARP is a nuclear enzyme, and 18 members of the PARP protein family that transfer PAR or mono-ADP-ribose to themselves and/or other target proteins have been identified; among them, PARP-1 plays a major role in the total activity. PARP-1 is considered a DNA nick sensor and occupies a central position in DNA SSBs, especially BER. […] PARP inhibitors (PARPis) can bind to the NAD+-binding pocket of PARP-1, produce conformational changes in PARP-1 and stabilize the combination of PARP-1 and DNA. This is referred to as the trapping of DNAPARP-1 complexes. […] Thus, it follows that PARPis could cause profound damage to SSB repair, while DSB repair plays a vital role in maintaining the integrity of genetic material, which in turn uses HRR as the optimum compensation pathway. Therefore, we can infer that tumor cells will not be able to repair DSBs in the case of HRR deficiency; moreover, under the action of PARPis, the defective cells eventually succumb to synthetic lethality.
#79 PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications | Molecular Cancer | Full Text
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-020-01167-9
According to this principle, PARP inhibitors have received great attention. PARP is a nuclear enzyme, and 18 members of the PARP protein family that transfer PAR or mono-ADP-ribose to themselves and/or other target proteins have been identified; among them, PARP-1 plays a major role in the total activity. PARP-1 is considered a DNA nick sensor and occupies a central position in DNA SSBs, especially BER. […] PARP inhibitors (PARPis) can bind to the NAD+-binding pocket of PARP-1, produce conformational changes in PARP-1 and stabilize the combination of PARP-1 and DNA. This is referred to as the trapping of DNAPARP-1 complexes. […] Thus, it follows that PARPis could cause profound damage to SSB repair, while DSB repair plays a vital role in maintaining the integrity of genetic material, which in turn uses HRR as the optimum compensation pathway. Therefore, we can infer that tumor cells will not be able to repair DSBs in the case of HRR deficiency; moreover, under the action of PARPis, the defective cells eventually succumb to synthetic lethality.
#80 PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications | Molecular Cancer | Full Text
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-020-01167-9
The loss of the wild-type BRCA allele, which is considered a classical tumor suppressor, increases the risks of breast cancer, ovarian cancer, and pancreatic cancer, among others. […] However, BRCA1/2 mutant cells cannot undergo DSB repair through HRR, resulting in genomic instability and cell death. […] Although PARPis have shown promise in monotherapy as well as combination therapy regimens in clinical trials for several cancers, as with other targeted therapies, the benefits of PARPis have been counteracted by the appearance of resistance. […] Because the mechanism of action of PARPis is related to HR deficiency, any methods that restore HR could lead to PARPi resistance in tumor cells. […] The only accepted PARPi for clinical application in pancreatic cancer is olaparib. According to the POLO trial, it has been used as a monotherapy for maintenance treatment in patients with metastatic pancreatic cancer who do not exhibit disease progression for 16 weeks after first-line, platinum-based chemotherapy.
#81 Mechanism for How Pancreatic Cancer Evades Immunotherapy Elucidated
https://lombardi.georgetown.edu/news-release/mechanism-for-how-pancreatic-cancer-evades-immunotherapy-elucidated/
Pancreatic cancer, one of the most lethal of all cancers, is capable of evading attacks by immune cells by changing its microenvironment so that the immune cells suppress, rather than support, an attack on the tumor, according to a study led by Georgetown Lombardi Comprehensive Cancer Center researchers. […] One reason for this treatment resistance is the tumor microenvironment of PDAC, which actively suppresses immune responses that are helpful in attacking cancer cells. […] Malignant pancreatic cells are simultaneously trying to find ways to evade a T cell immune attack by influencing components of the tumor microenvironment to favor cancer development and growth, a process called remodeling. […] Beyond the finding of remodeling and evasion, the research team was able to determine that one of the mediators of this suppressive response included an activated protein called signal transducer and activator of transcription 1 (STAT1).
#82 Mechanism for How Pancreatic Cancer Evades Immunotherapy Elucidated
https://lombardi.georgetown.edu/news-release/mechanism-for-how-pancreatic-cancer-evades-immunotherapy-elucidated/
Pancreatic cancer, one of the most lethal of all cancers, is capable of evading attacks by immune cells by changing its microenvironment so that the immune cells suppress, rather than support, an attack on the tumor, according to a study led by Georgetown Lombardi Comprehensive Cancer Center researchers. […] One reason for this treatment resistance is the tumor microenvironment of PDAC, which actively suppresses immune responses that are helpful in attacking cancer cells. […] Malignant pancreatic cells are simultaneously trying to find ways to evade a T cell immune attack by influencing components of the tumor microenvironment to favor cancer development and growth, a process called remodeling. […] Beyond the finding of remodeling and evasion, the research team was able to determine that one of the mediators of this suppressive response included an activated protein called signal transducer and activator of transcription 1 (STAT1).
#83 Mechanism for How Pancreatic Cancer Evades Immunotherapy Elucidated
https://lombardi.georgetown.edu/news-release/mechanism-for-how-pancreatic-cancer-evades-immunotherapy-elucidated/
Pancreatic cancer, one of the most lethal of all cancers, is capable of evading attacks by immune cells by changing its microenvironment so that the immune cells suppress, rather than support, an attack on the tumor, according to a study led by Georgetown Lombardi Comprehensive Cancer Center researchers. […] One reason for this treatment resistance is the tumor microenvironment of PDAC, which actively suppresses immune responses that are helpful in attacking cancer cells. […] Malignant pancreatic cells are simultaneously trying to find ways to evade a T cell immune attack by influencing components of the tumor microenvironment to favor cancer development and growth, a process called remodeling. […] Beyond the finding of remodeling and evasion, the research team was able to determine that one of the mediators of this suppressive response included an activated protein called signal transducer and activator of transcription 1 (STAT1).
#84 Mechanism for How Pancreatic Cancer Evades Immunotherapy Elucidated
https://lombardi.georgetown.edu/news-release/mechanism-for-how-pancreatic-cancer-evades-immunotherapy-elucidated/
Pancreatic cancer, one of the most lethal of all cancers, is capable of evading attacks by immune cells by changing its microenvironment so that the immune cells suppress, rather than support, an attack on the tumor, according to a study led by Georgetown Lombardi Comprehensive Cancer Center researchers. […] One reason for this treatment resistance is the tumor microenvironment of PDAC, which actively suppresses immune responses that are helpful in attacking cancer cells. […] Malignant pancreatic cells are simultaneously trying to find ways to evade a T cell immune attack by influencing components of the tumor microenvironment to favor cancer development and growth, a process called remodeling. […] Beyond the finding of remodeling and evasion, the research team was able to determine that one of the mediators of this suppressive response included an activated protein called signal transducer and activator of transcription 1 (STAT1).
#85 Mechanism for How Pancreatic Cancer Evades Immunotherapy Elucidated
https://lombardi.georgetown.edu/news-release/mechanism-for-how-pancreatic-cancer-evades-immunotherapy-elucidated/
The researchers hypothesized that STAT1-based signaling could be targeted to reverse this resistance mechanism. […] Indeed, use of the drug overcame tumor-protective remodeling responses and helped improve the response to immunotherapy. […] This approach to treating an aggressive cancer is promising and we hope that it can be tested in clinical trials in the not-too-distant future.
#86 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
The PDAC microenvironment is highly intricate and heterogeneous. […] PDAC cells are surrounded by dense proliferating connective tissue, which is composed of collagen mesh, leading to hypoxia and nutrient deficiency in tumours. […] Immune cells are important components of the TME, and continuously activated inflammatory pathways can promote the occurrence of cancer. […] The infiltration and activation of tumour-associated macrophages (TAMs) can promote immune evasion and matrix remodelling in PDAC. […] The metabolic regulatory role of small extracellular vesicles (sEVs), such as exosomes, as intercellular communication mediators in tumours should not be ignored. […] Pancreatic cancer-derived extracellular vesicles may influence lipolysis to induce cancer-related cachexia. […] In addition to local metabolic reprogramming in tumours, systemic metabolism can also serve as a potential pathogenic mechanism and therapeutic target. […] Obesity and diabetes are increasingly recognized as risk factors for PDAC, not only because of the remodelling of the tumour microenvironment but also because of their effects on systemic metabolism.
#87 Emerging mechanisms and promising approaches in pancreatic cancer metabolism | Cell Death & Disease
https://www.nature.com/articles/s41419-024-06930-0
Metabolic syndrome (MetS), a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidaemia, is associated with the risk of PDAC. […] Stress adaptation through phase-separated organelle stress granules (SGs) mediates the development of PDAC, and obesity may be a driving force behind this process. […] Recent studies have discovered new forms of regulated cell death resulting from imbalances in cellular metabolism. […] Although the role of metabolic cell death is controversial, these may provide insights for novel therapeutic interventions. […] Given that most of the current understanding of how metabolism supports cell proliferation is based on studies in cancer cells, how metabolism shapes the interactions of different cells needs to be explored in more complex ecosystems.
#88 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
In conclusion, the understanding of autophagys regulatory mechanisms has deepened over the past decade with the discovery of new regulatory networks and transduction pathways. […] The pathophysiological role of autophagy in cancer, specifically pancreatic cancer, has also been explored. Changes in autophagy play an important role in the onset and development of pancreatic cancer. […] This finding in autophagy defective mice suggests that the autophagy process can be an effective intervention target to prevent and treat pancreatic cancer. […] Inhibition of autophagy may be an important direction of targeted therapy for pancreatic cancer in the future, and the development and use of autophagy inhibitors should be a priority.
#89 The role and mechanism of autophagy in pancreatic cancer | CMAR
https://www.dovepress.com/the-role-and-mechanism-of-autophagy-in-pancreatic-cancer-an-update-rev-peer-reviewed-fulltext-article-CMAR
In conclusion, the understanding of autophagys regulatory mechanisms has deepened over the past decade with the discovery of new regulatory networks and transduction pathways. […] The pathophysiological role of autophagy in cancer, specifically pancreatic cancer, has also been explored. Changes in autophagy play an important role in the onset and development of pancreatic cancer. […] This finding in autophagy defective mice suggests that the autophagy process can be an effective intervention target to prevent and treat pancreatic cancer. […] Inhibition of autophagy may be an important direction of targeted therapy for pancreatic cancer in the future, and the development and use of autophagy inhibitors should be a priority.
#90 Uncovering the Mechanism for Drug Resistance in Pancreatic Cancer | University of Virginia School of Engineering and Applied Science
https://engineering.virginia.edu/news-events/news/uncovering-mechanism-drug-resistance-pancreatic-cancer
We found that once the cancer cells undergo this transition under hypoxic conditions, they become much more likely to resist chemotherapy. […] This research represents a significant potential advance for pancreatic ductal adenocarcinoma treatment. The ability to disrupt the durable, hypoxia-induced changes in pancreatic cancer cells offers a potential breakthrough in improving patient outcomes. […] By targeting the pathways that enable cancer cells to resist chemotherapy, we hope to bring new, more effective treatments to patients with pancreatic cancer.
#91 Uncovering the Mechanism for Drug Resistance in Pancreatic Cancer | University of Virginia School of Engineering and Applied Science
https://engineering.virginia.edu/news-events/news/uncovering-mechanism-drug-resistance-pancreatic-cancer
We found that once the cancer cells undergo this transition under hypoxic conditions, they become much more likely to resist chemotherapy. […] This research represents a significant potential advance for pancreatic ductal adenocarcinoma treatment. The ability to disrupt the durable, hypoxia-induced changes in pancreatic cancer cells offers a potential breakthrough in improving patient outcomes. […] By targeting the pathways that enable cancer cells to resist chemotherapy, we hope to bring new, more effective treatments to patients with pancreatic cancer.