Guzy neuroendokrynne – Patofizjologia i mechanizm

Guzy neuroendokrynne
Patofizjologia i mechanizm

Guzy neuroendokrynne (NETs) to heterogeniczna grupa nowotworów wywodzących się z komórek neuroendokrynnych, najczęściej lokalizujących się w przewodzie pokarmowym, trzustce i płucach, stanowiąca około 2% wszystkich nowotworów złośliwych w USA. Klasyfikacja WHO z 2022 roku rozróżnia dobrze zróżnicowane NETs od słabo zróżnicowanych raków neuroendokrynnych (NECs) na podstawie liczby mitoz (na 2 mm²) oraz indeksu Ki-67, co ma istotne znaczenie prognostyczne i terapeutyczne. Patogeneza NETs obejmuje kluczowe szlaki sygnałowe, takie jak PI3K/AKT/mTOR, angiogenezę zależną od VEGF oraz szlaki Notch, Hedgehog i Wnt. W trzustkowych NETs (PNETs) dominują mutacje genów MEN1, ATRX, DAXX, TSC2, PTEN i PIK3CA, a epigenetyczne modyfikacje odgrywają istotną rolę w regulacji wzrostu i progresji guza. Mikrośrodowisko guza, w tym fibroblasty związane z rakiem (CAFs) i makrofagi związane z guzem (TAMs), wpływa na rozwój zwłóknienia i immunosupresję, co ma znaczenie dla odpowiedzi na terapię.

Wprowadzenie do guzów neuroendokrynnych

Guzy neuroendokrynne (NETs) stanowią heterogeniczną grupę nowotworów wywodzących się z komórek układu endokrynnego (hormonalnego) i nerwowego. Mogą one występować w różnych narządach, najczęściej w przewodzie pokarmowym, gdzie często nazywane są rakowikami, ale spotykane są również w trzustce, płucach i innych częściach ciała. Stanowią one około 2% wszystkich nowotworów złośliwych w Stanach Zjednoczonych.¹²

Komórki tych nowotworów charakteryzują się podobnym wyglądem histologicznym, posiadają specjalne ziarnistości wydzielnicze i często produkują aminy biogenne oraz hormony polipeptydowe. NETs powstają z różnych komórek neuroendokrynnych, których normalną funkcją jest działanie na styku neuroendokrynnym. Komórki neuroendokrynne są obecne nie tylko w gruczołach endokrynnych, które produkują hormony, ale znajdują się we wszystkich tkankach organizmu.³

Znaczna część pacjentów z guzami neuroendokrynnymi doświadcza zaburzeń endokrynnych będących następstwem zwiększonego wydzielania amin lub hormonów peptydowych, co wpływa na ich jakość życia i rokowanie. W ostatniej dekadzie kategoryzacja patologiczna, techniki diagnostyczne i opcje terapeutyczne dla NETs, zarówno dobrze zróżnicowanych guzów neuroendokrynnych, jak i słabo zróżnicowanych raków neuroendokrynnych (NECs), znacząco ewoluowały.⁴

Klasyfikacja guzów neuroendokrynnych

Klasyfikacja guzów neuroendokrynnych była wielokrotnie aktualizowana w ostatnich latach, a najnowsza wersja pochodzi z klasyfikacji WHO nowotworów endokrynnych i neuroendokrynnych z 2022 roku. Kryteria diagnostyczne dla klasyfikacji NETs opierają się głównie na dwóch komponentach cyklu komórkowego:⁵⁶

Liczba mitoz – określana przez liczbę dzielących się komórek obserwowanych na określonym obszarze pod mikroskopem (2 mm²)⁷
Indeks Ki-67 – gdzie Ki-67 jest białkiem, którego ilość wzrasta wraz z przygotowaniem komórek do podziału⁸

Zasadniczo komórki nowotworowe, które zachowują molekularne i morfologiczne cechy komórek neuroendokrynnych, są dobrze zróżnicowane i nazywane są nowotworami neuroendokrynnymi (NETs). Agresywny nowotwór, który łączy zarówno rozpoznawalną część neuroendokrynną, jak i nieneuroendokrynną, określa się jako mieszany nowotwór neuroendokrynno-nieneuroendokrynny (MiNENs).⁹

Kluczową cechą nowej klasyfikacji jest rozróżnienie między zróżnicowanymi guzami neuroendokrynnymi (NETs), nazywanymi w niektórych systemach guzami rakowiakowymi, a słabo zróżnicowanymi rakami neuroendokrynnymi (NECs), ponieważ oba te typy wykazują wspólną ekspresję markerów neuroendokrynnych. Ten dychotomiczny podział morfologiczny na NETs i NECs jest poparty dowodami genetycznymi w specyficznych miejscach anatomicznych, a także różnicami klinicznymi, epidemiologicznymi, histologicznymi i prognostycznymi.¹⁰

Różnice między NETs i NECs

Termin nowotwory neuroendokrynne (NENs) obejmuje zarówno dobrze zróżnicowane NETs, jak i słabo zróżnicowane NECs, ponieważ oba typy wykazują wspólne cechy histologiczne, immunofenotypowe i ultrastrukturalne. Jednak dowody genetyczne w określonych miejscach anatomicznych potwierdzają podwójny podział morfologiczny, który odróżnia słabo zróżnicowane NECs od dobrze zróżnicowanych NETs.¹¹

Chociaż mogą mieć nakładające się cechy histologiczne, ich włączenie do jednej klasyfikacji może błędnie sugerować, że dobrze zróżnicowane NETs i słabo zróżnicowane NECs są blisko spokrewnionymi nowotworami. W większości narządów, w których badano te rodziny nowotworów, dane sugerują, że nie są one biologicznie blisko spokrewnione. Poza różnymi stopniami agresywności biologicznej i różnymi odpowiedziami na terapię medyczną, NETs i NECs mają różne czynniki ryzyka, predyspozycje dziedziczne, związki z nowotworami nie-neuroendokrynnymi i odmienne genetyczne podłoże.¹²

Z genetycznego punktu widzenia, NECs mają inaktywację RB1 i TP53, które natomiast rzadko występują w NETs. Dziedziczne zespoły NET występują w podobnych wzorcach, gdzie głównie dwie ścieżki są zaangażowane: regulacja cyklu komórkowego zależnego od cyklin (szczególnie w MEN1 i MEN4) oraz zaangażowanie ścieżki PI3K/mTOR.¹³

Patogeneza guzów neuroendokrynnych

Patogeneza guzów neuroendokrynnych jest złożona i nie została jeszcze w pełni wyjaśniona. Badania genomowe NETs sugerują, że ścieżki regulujące remodelowanie chromatyny i modyfikacje epigenetyczne mogą odgrywać kluczową rolę w regulacji wzrostu NET. Obserwacje te oferują potencjał dla nowych postępów terapeutycznych i diagnostycznych dla pacjentów z NETs.¹⁴¹⁵

Szlaki sygnałowe w patogenezie NETs

W patogenezie NETs zaangażowanych jest kilka kluczowych szlaków sygnałowych:¹⁶

Szlak PI3K/AKT/mTOR – odgrywa centralną rolę w patogenezie i progresji NETs, a badania kliniczne wykazały bezpieczeństwo i skuteczność inhibitorów mTOR u pacjentów z NET. Trzy najczęściej upośledzone szlaki sygnałowe w trzustkowych NETs obejmują szlak PI3K/AKT/mTOR, szlak T53/Rb oraz szlak remodelowania chromatyny.¹⁷¹⁸
Angiogeneza – mikrośrodowisko guza neuroendokrynnego jest napędzane częściowo przez VEGF i naczynia krwionośne. Te nowotwory neuroendokrynne wymagają odżywienia przez naczynia krwionośne, aby rosnąć i rozprzestrzeniać się. W ostatniej dekadzie nastąpił silny nacisk na stosowanie inhibitorów VEGF w celu zahamowania angiogenezy i zapobiegania wzrostowi i rozprzestrzenianiu się nowotworów.¹⁹²⁰
Szlak Notch, Hedgehog i Wnt – wszystkie te szlaki są zaangażowane zarówno w chorobach zwłóknieniowych, jak i nowotworowych, i mają znaczenie w patogenezie NETs, choć dokładna rola szlaku Hedgehog w rozwoju zwłóknienia krezkowego pozostaje nieustalona. Badania nad szlakiem Notch w SI-NETs in vivo są sprzeczne, a wyniki sugerują niewielką rolę szlaku Wnt/β-kateniny w rozwoju SI-NET i zwłóknieniu.²¹

Genetyczne podłoże NETs

Większość guzów neuroendokrynnych trzustki (PNETs) występuje sporadycznie (90%). Jednak mogą one być częścią zespołów dziedzicznych:²²

Zespół mnogiej gruczolakowatości wewnątrzwydzielniczej typu 1 (MEN1)
Choroba von Hippla-Lindaua (VHL)
Choroba von Recklinghausena lub neurofibromatoza typu 1 (NF-1)
Stwardnienie guzowate (TSC)

W tych przypadkach podstawowe nieprawidłowości genetyczne odgrywają znaczącą rolę w rozwoju PETs, które często są wieloogniskowe. Cechy patologiczne rodzinnych/dziedzicznych PETs są generalnie podobne do postaci sporadycznej, chociaż PETs występujące u pacjentów z zespołem VHL mogą mieć cechy komórek jasnych.²³

Mutacja germinalna MEN-1 z utratą funkcji prowadzi do powstania licznych mikrogruczolaków, głównie skutkujących niefunkcjonalnymi PETs i insulinoma. Mutacje NF-1 lub TSC1/2 prowadzą do utraty funkcji ich produktów białkowych – odpowiednio neurofibrominy i tuberyny. Co istotne, nienaruszone białka hamują funkcję wspólnego celu, mianowicie mTOR (mammalian target of rapamycin).²⁴

Ponadto, aktywacja mTOR zależna od czynnika indukowanego hipoksją (HIF) łączy zaburzone sygnalizowanie mTOR z chorobą VHL. mTOR jest kluczowym regulatorem wzrostu komórek i integruje szeroką gamę bodźców komórkowych, takich jak czynniki wzrostu, składniki odżywcze, stan energetyczny i stres wywołany hipoksją, co czyni go dobrym celem terapeutycznym dla PETs.²⁵

Zróżnicowanie podtypów NETs

Guzy neuroendokrynne przewodu pokarmowego (GEP-NETs) klasyfikowane są według statusu zróżnicowania guza i stopnia guza. Terminologia GEP-NENs ewoluowała, aby odzwierciedlić podział na dobrze zróżnicowane guzy neuroendokrynne (NETs) i słabo zróżnicowane raki neuroendokrynne (NECs). Chociaż NETs żołądkowo-jelitowe i NETs trzustki mogą mieć podobne cechy w rutynowej ocenie histologicznej, mają one różną patogenezę i biologię.²⁶

Zróżnicowanie NETs może wpływać także na ich odpowiedź na immunoterapię. Agresywne nowotwory neuroendokrynne wydają się reagować na inhibitory punktów kontrolnych, co sugeruje, że ich środowisko nie jest szczególnie immunosupresyjne. Istotnym pytaniem jest, czy można zmienić to środowisko i potencjalnie sprawić, by niskograde’owe nowotwory neuroendokrynne reagowały na immunoterapię.²⁷

Mikrobiom guza w NETs

Mikrośrodowisko guza (TME) odgrywa kluczową rolę w patogenezie NETs i stanowi interesujący obszar badań. Mikrośrodowisko guza w NETs różni się od innych nowotworów, z charakterystyczną reakcją desmoplastyczną i ograniczoną infiltracją leukocytową.²⁸

Komponenty mikrobiologiczne w patogenezie NETs

Główne komponenty mikrobiologiczne w patogenezie NETs obejmują:²⁹³⁰

Fibroblasty związane z rakiem (CAFs) – identyfikowane przez ekspresję α-aktyny mięśni gładkich (SMA). W NETs jelita cienkiego, CAFs są ważnymi regulatorami programów stromalnych zwłóknienia.³¹
Makrofagi związane z guzem (TAMs) – główny składnik infiltratu leukocytowego w mikrośrodowisku guza. TAMs generalnie mają rolę sprzyjającą rozwojowi guza, tłumią układ odpornościowy adaptacyjny i stymulują zwłóknienie poprzez wydzielanie czynników prozwłóknieniowych, takich jak TGF.³²
Macierz zewnątrzkomórkowa (ECM) – komórki EC i komórki BON1 (linia komórkowa trzustkowego NET) są mechanowrażliwe, a stres mechaniczny wpływa na uwalnianie cząsteczek sygnałowych, takich jak serotonina. Zmiany w składzie ECM mogą wpływać na funkcjonalność guza w SI-NETs poprzez sygnały biochemiczne i biomechaniczne.³³

Czynniki wzrostu w patogenezie NETs

W patogenezie NETs istotną rolę odgrywają również czynniki wzrostu o znanym działaniu prozwłóknieniowym:³⁴³⁵³⁶

Serotonina – jest aminą biogenną, która może działać jako neuroprzekaźnik, hormon lub czynnik wzrostu. Możliwość wywoływania przez serotoninę szerokiego spektrum efektów przypisuje się jej zróżnicowanemu systemowi receptorowemu. Związek przyczynowy między serotoniną a zwłóknieniem sugeruje dodatkowo związek powikłań zwłóknieniowych z lekami celującymi w receptor 5-HT2B, takimi jak metyzergid, lek przeciwmigrenowy.³⁷
Rodzina cytokin TGF – kluczowy regulator procesów proliferacyjnych i prozwłóknieniowych. Sygnalizacja TGF ma podwójną rolę: z jednej strony przeciwnowotworową i antyproliferacyjną w warunkach fizjologicznych i wczesnych stanach nowotworowych, a z drugiej – pronowotworowe efekty, takie jak proliferacja i inwazja w późniejszych stadiach choroby złośliwej. Ze względu na swoje działanie prozwłóknieniowe i pronowotworowe, TGF jest jednym z najbardziej intensywnie badanych czynników wzrostu w SI-NETs.³⁸
PDGF – ma silny efekt proliferacyjny na fibroblasty i może indukować proliferację komórek nabłonkowych raka. Jego efekty prozwłóknieniowe są pośredniczone przez wiązanie z receptorami PDGF α i β.³⁹
FGF2 – jest ważnym regulatorem gojenia ran i ma silne działanie mitogenne na fibroblasty.⁴⁰
TGF i naskórkowy czynnik wzrostu (EGF) – są ligandami EGFR, receptora kinazy tyrozynowej.⁴¹
CTGF – członek rodziny czynników wzrostu CCN, które są indukowane przez cytokiny, takie jak TGF, a także przez serotoninę.⁴²

Szczegółowe mechanizmy molekularne w NETs

Badania molekularne ujawniły szereg mechanizmów zaangażowanych w patogenezę NETs, co może prowadzić do opracowania nowych strategii terapeutycznych.⁴³

Mutacje genetyczne w NETs trzustki

Analiza somatycznych mutacji DNA w dobrze zróżnicowanych guzach neuroendokrynnych trzustki zidentyfikowała cztery ważne odkrycia:⁴⁴

Geny zmutowane w NETs, MEN1, ATRX, DAXX, TSC2, PTEN i PIK3CA, różnią się od zmutowanych genów wcześniej znalezionych w gruczolakoraku trzustki
Mutacje wpływające na nowy szlak nowotworowy obejmujący geny ATRX i DAXX znaleziono w około 40% trzustkowych NETs
Mutacje ATRX/DAXX i MEN1 były związane z lepszym rokowaniem

Sporady NETs endokrynologicznych trzustki charakteryzują się także specyficznymi zmianami genetycznymi. Analizy genomowe metodą porównawczej hybrydyzacji genomowej (CGH) wskazują, że utraty chromosomów występują nieco częściej niż zyski, podczas gdy amplifikacje są rzadkie. Utraty chromosomu 1 i 11q, a także zyski 9q wydają się być wczesnymi wydarzeniami w rozwoju guzów trzustki.⁴⁵

Te odkrycia wskazują na szlak supresji nowotworów i niestabilność chromosomową jako ważne mechanizmy związane ze złośliwością guzów endokrynnych trzustki. Niedawne badania z wykorzystaniem analizy polimorfizmu pojedynczych nukleotydów (SNP) w całym genomie wykazały, że około 30-40% guzów endokrynnych trzustki ma wysokie zaburzenia genetyczne określone przez aberracje chromosomowe.⁴⁶

Rola epigenetyki w patogenezie NETs

Epigenetyczne modyfikacje odgrywają kluczową rolę w kształtowaniu złożonego krajobrazu sygnalizacji w NETs trzustki (PNET). Modyfikacje epigenetyczne mogą prowadzić do nieprawidłowych wzorców ekspresji genów, przyczyniając się do niekontrolowanego wzrostu komórek, unikania śmierci komórkowej i zwiększonego potencjału przerzutowego – charakterystycznych cech raka.⁴⁷

Wkład tych modyfikacji epigenetycznych w patologię PNET nie został jeszcze w pełni zbadany. Unikalną cechą PNETs jest również powolny wzrost, co stanowi praktyczne wyzwanie dla prac badawczych w laboratoriach. Mimo wyzwań osiągnięto pewne obiecujące postępy, w tym rozpoznanie ograniczonej skuteczności leków przeciwnowotworowych działających epigenetycznie, co skłoniło do badań nad łączeniem tych terapii z istniejącymi lub nowymi ukierunkowanymi terapiami dla synergistycznego i kombinacyjnego podejścia.⁴⁸

Mikrobiom guza w NETs trzustki

Mikrośrodowisko guza trzustkowego neuroendokrynnego to środowisko sprzyjające rozwojowi guza, składające się z komórek nowotworowych, komórek odpornościowych/immunosupresyjnych i macierzy zewnątrzkomórkowej, charakteryzujące się wyraźną cechą immunosupresji. Może prowadzić do ucieczki immunologicznej, inwazji i przerzutów komórek nowotworowych poprzez hamowanie odpowiedzi immunologicznej przeciwnowotworowej i promowanie angiogenezy, a także jest główną przyczyną oporności na leki w leczeniu przeciwnowotworowym.⁴⁹

Analiza RNA-Seq wykazała, że pierwotne guzy przerzutowych PNET wykazywały znaczną aktywację ścieżek związanych z zapaleniem i układem odpornościowym. Określono, że przerzutowe PNET charakteryzowały się zwiększoną liczbą limfocytów T infiltrujących guzy w porównaniu z guzami zlokalizowanymi. Limfocyty T izolowane zarówno z zlokalizowanych, jak i przerzutowych PNET wykazywały dowody rekrutacji i aktywacji zależnej od antygenu, co sugeruje środowisko przepuszczalne dla układu odpornościowego.⁵⁰

Analiza obliczeniowa sugerowała, że worinostat, inhibitor deacetylazy histonowej, może zaburzać sygnaturę transkryptomiczną przerzutowych PNET. Leczenie worinostatem tkanek przerzutowych PNET pochodzących od pacjentów zwiększało rekrutację autologicznych limfocytów T, co zostało potwierdzone w mysim modelu PNET. Farmakologiczna indukcja ekspresji chemokin może stanowić obiecujące podejście do zwiększenia immunogenności przerzutowych środowisk PNET.⁵¹

Zwłóknienie w patogenezie NETs

Guzy neuroendokrynne jelita cienkiego (SI-NETs) charakteryzują się zdolnością do wydzielania amin biogennych i peptydów, które powodują wyraźną patologię kliniczną, w tym zespół rakowiaka, charakteryzujący się biegunką i napadami zaczerwienienia, a także zwłóknieniem, zwłaszcza zwłóknieniem krezkowym.⁵²

Mechanizmy zwłóknienia w NETs

Kolejną cechą charakterystyczną SI-NETs jest zdolność do indukcji zwłóknienia. Zwłóknienie może występować wokół guza lub w odległych miejscach. Zwłóknienie krezkowe (MF) jest najbardziej godne uwagi i występuje u do 50% pacjentów z SI-NET. Ponieważ przeżywalność pacjentów poprawiła się od czasu opracowania ukierunkowanych i bardziej skutecznych terapii zespołu rakowiaka i kontroli wzrostu guza, istnieje zwiększona potrzeba postępu w opcjach leczenia MF.⁵³

Caplin kieruje projektem współpracy między dwoma wiodącymi w Europie Centrami Doskonałości Europejskiego Towarzystwa Guzów Neuroendokrynnych – The Royal Free-UCL London i Erasmus University Medical Center w Rotterdamie – w celu zbadania podstawowej przyczyny molekularnej zwłóknienia krezkowego. Program badawczy ma na celu zbadanie czynników i ścieżek zaangażowanych w rozwój zwłóknienia krezkowego (MF) związanego z guzami neuroendokrynnymi jelita cienkiego (SI-NET).⁵⁴

Badania będą dotyczyć interakcji między komórkami SI-NET a fibroblastami związanymi z rakiem (komórkami wytwarzającymi czynniki zwłóknieniowe) oraz oceny modulującego wpływu steroidów płciowych na fibrogenezę. Te badania dostarczą wglądu w przyczynę MF i mogą doprowadzić do opracowania biomarkerów (predykcyjnych) dla MF, a także identyfikacji nowych celów terapeutycznych w celu zahamowania wzrostu komórek i rozwoju zwłóknienia.⁵⁵

Przyszłość badań nad NETs

Terapia dla NETs postępuje ostatnio w oparciu o lepsze zrozumienie molekularne, w tym zaangażowanie mTOR, VEGF i terapii radioizotopowej znakowanymi peptydami (PRRT), co potwierdza dalszą możliwość leczenia poza całkowitą resekcją.⁵⁶⁵⁷

Nowe podejścia terapeutyczne

Opracowanie nowszych i ewoluujących opcji leczenia w oparciu o lepsze zrozumienie na poziomie molekularnym, w tym mTOR, VEGF i PRRT, dodaje dowodów potwierdzających dalszą możliwość dogłębnych badań i identyfikacji większej liczby opcji leczenia poza całkowitą resekcją tych guzów.⁵⁸

Obecna terapia systemowa dla NETs głównie ukierunkowuje proliferację guza i produkcję hormonów. Rozległe badania w tej dziedzinie pozwoliły na identyfikację różnych celów lekowych, które zostały wykorzystane przy użyciu obecnie zatwierdzonych i testowanych cząsteczek.⁵⁹

Badacze w Memorial Sloan Kettering badają nowe podejścia do leczenia z wykorzystaniem mysiego modelu, który wykazuje guzy neuroendokrynne trzustki. Model ten będzie wykorzystywany do przeprowadzania wczesnych testów nowych terapii lekowych i ukierunkowanych terapii opartych na przeciwciałach. Model guza neuroendokrynnego trzustki będzie również wykorzystywany do testowania nowej klasy leków, które mogą mieć potencjał do blokowania produkcji białka zwanego proteazami katepsyny, które, jak się uważa, promują wzrost guzów neuroendokrynnych trzustki.⁶⁰

Biomarkery i personalizacja leczenia

Projekt prowadzony w laboratorium Prof. Meyera wykazał po raz pierwszy, że krążące komórki nowotworowe (CTCs) były wykrywalne we krwi pacjentów z różnymi NETs, a ich obecność wskazywała na niekorzystne rokowanie. Postępy w technologii umożliwiają obecnie przeprowadzanie szczegółowej charakterystyki molekularnej na pojedynczych komórkach, a projekt porównuje zmiany genetyczne obserwowane w pierwotnej tkance guza z tymi obserwowanymi w CTCs, a także z cfDNA (fragmentami DNA, które pochodzą z guza i można je znaleźć krążące w krwiobiegu).⁶¹

Jeśli można wykazać, że CTCs i cfDNA rzeczywiście dokładnie reprezentują guz, będzie można śledzić, jak guz ewoluuje w czasie i podczas leczenia. Może to pozwolić klinicystom leczącym pacjentów z NETs na wybór odpowiedniej terapii i przewidywanie pojawienia się oporności.⁶²

Zrozumienie heterogeniczności szlaków sygnałowych w różnych NET jest kluczowe dla projektowania odpowiednich badań klinicznych. Istnieją dowody na preferencyjną ekspresję NOTCH1 i jego efektorów downstream, HES1 i HEY1, w rektalnych guzach neuroendokrynnych i podzbiorze trzustkowych guzów neuroendokrynnych. Wyniki potwierdzają heterogeniczność szlaków sygnałowych guzów neuroendokrynnych żołądkowo-jelitowych, podkreślając potrzebę krytycznej oceny szlaków sygnałowych w zależności od umiejscowienia przy projektowaniu badań klinicznych dla guzów neuroendokrynnych żołądkowo-jelitowych.⁶³

Optymalizacja terapii angiogennej w NETs trzustki pozostaje otwartym pytaniem; w szczególności nie zidentyfikowano jasnego klinicznego punktu końcowego dla terapii bewacyzumabem w tym kontekście onkologicznym, podobnie jak pełnego spektrum zdarzeń niepożądanych związanych z jego stosowaniem. Badania podstawowe, mające na celu wyjaśnienie mechanizmów oporności i znalezienie markerów odpowiedzi, są niezbędne w najbliższej przyszłości dla zaprojektowania bardziej odpowiednich i spersonalizowanych badań klinicznych.⁶⁴

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Materiały źródłowe

#1 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. […] Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. […] The secretion of this hormone is regulated by complex mechanisms, as described in Figure 2. […] The classification of NEN has been updated multiple times over recent years with the latest update being the WHO Classification of Endocrine and NEN in 2022.
#2 Neuroendocrine tumor – Wikipedia
https://en.wikipedia.org/wiki/Neuroendocrine_tumor
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body. […] Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, including a similar histological appearance, having special secretory granules, and often producing biogenic amines and polypeptide hormones. […] NETs are believed to arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormones, but are found in all body tissues.
#3 Neuroendocrine tumor – Wikipedia
https://en.wikipedia.org/wiki/Neuroendocrine_tumor
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body. […] Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, including a similar histological appearance, having special secretory granules, and often producing biogenic amines and polypeptide hormones. […] NETs are believed to arise from various neuroendocrine cells whose normal function is to serve at the neuroendocrine interface. Neuroendocrine cells are present not only in endocrine glands throughout the body that produce hormones, but are found in all body tissues.
#4 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. […] A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. […] Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) have appreciably evolved. […] Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection.
#5 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
The secretion of this hormone is regulated by complex mechanisms, as described in Figure 2. […] The classification of NEN has been updated multiple times over recent years with the latest update being the WHO Classification of Endocrine and NEN in 2022. […] Essentially, tumor cells that retain the molecular and morphological features of neuroendocrine cells, are well differentiated and are termed neuroendocrine neoplasms (NETs). […] An aggressive neoplasm that combines both a recognizable neuroendocrine and non-neuroendocrine part is labeled a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNENs). […] The diagnostic criteria for the classification of NENs are mainly based on two components of the cell cycle: the mitotic count, determined by the number of cells that are dividing observed in a specific area under a microscope (2 mm2), and the Ki-67 index, where Ki-67 is a protein that increases in amount as the cells prepare themselves to divide.
#6 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. They account for 2% of all malignancies in the United States. A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. […] Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection. […] The secretion of this hormone is regulated by complex mechanisms, as described in Figure 2. […] The classification of NEN has been updated multiple times over recent years with the latest update being the WHO Classification of Endocrine and NEN in 2022.
#7 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
The diagnostic criteria for the classification of NENs are mainly based on two components of the cell cycle: the mitotic count, determined by the number of cells that are dividing observed in a specific area under a microscope (2 mmÂ²), and the Ki-67 index, where Ki-67 is a protein that increases in amount as the cells prepare themselves to divide. […] The heterogeneous behavior of NENs makes it challenging to devise a practical staging system that can help by providing accurate prognostic information. […] The recent classification has adopted the separation of well-differentiated NET G3 from NEC. The pancreatic NEC (panNEC; pancreatic neuroendocrine neoplasm NEN-G3) is classified into neuroendocrine tumor-G3 and NEC-G3. The distinction is clinically significant since the two respond differently to chemotherapy.
#8 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
The diagnostic criteria for the classification of NENs are mainly based on two components of the cell cycle: the mitotic count, determined by the number of cells that are dividing observed in a specific area under a microscope (2 mmÂ²), and the Ki-67 index, where Ki-67 is a protein that increases in amount as the cells prepare themselves to divide. […] The heterogeneous behavior of NENs makes it challenging to devise a practical staging system that can help by providing accurate prognostic information. […] The recent classification has adopted the separation of well-differentiated NET G3 from NEC. The pancreatic NEC (panNEC; pancreatic neuroendocrine neoplasm NEN-G3) is classified into neuroendocrine tumor-G3 and NEC-G3. The distinction is clinically significant since the two respond differently to chemotherapy.
#9 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
The secretion of this hormone is regulated by complex mechanisms, as described in Figure 2. […] The classification of NEN has been updated multiple times over recent years with the latest update being the WHO Classification of Endocrine and NEN in 2022. […] Essentially, tumor cells that retain the molecular and morphological features of neuroendocrine cells, are well differentiated and are termed neuroendocrine neoplasms (NETs). […] An aggressive neoplasm that combines both a recognizable neuroendocrine and non-neuroendocrine part is labeled a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNENs). […] The diagnostic criteria for the classification of NENs are mainly based on two components of the cell cycle: the mitotic count, determined by the number of cells that are dividing observed in a specific area under a microscope (2 mm2), and the Ki-67 index, where Ki-67 is a protein that increases in amount as the cells prepare themselves to divide.
#10 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal | Modern Pathology
https://www.nature.com/articles/s41379-018-0110-y
The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. […] The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. […] This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. […] The difficulty of specifically predicting the behavior of well-differentiated NENs is well-known, and although organ-specific grading schemes have aided in stratifying relative aggressiveness, the proposed conceptual terminology expressly avoids categorizing the neoplasms as explicitly benign or malignant.
#11 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal | Modern Pathology
https://www.nature.com/articles/s41379-018-0110-y
The term NENs encompasses both well-differentiated NETs and poorly differentiated NECs, as they both share common histologic, immunophenotypic, and ultrastructural neuroendocrine features. […] However, genetic evidence at specific anatomic sites supports the dual morphological subdivision that distinguishes poorly differentiated NECs from well-differentiated NETs. […] Although they can have overlapping histologic features, their inclusion together in a single classification framework may incorrectly lead to the presumption that well-differentiated NETs and poorly differentiated NECs are closely related neoplasms; in most organs where these families of neoplasms have been studied, the data suggest that they are not biologically closely related. […] In addition, to have different degrees of biological aggressiveness, and different responses to medical therapy, NETs and NECs have different risk factors, hereditary predispositions, relationships to non-NE neoplasia, and underpinning genetics.
#12 A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal | Modern Pathology
https://www.nature.com/articles/s41379-018-0110-y
The term NENs encompasses both well-differentiated NETs and poorly differentiated NECs, as they both share common histologic, immunophenotypic, and ultrastructural neuroendocrine features. […] However, genetic evidence at specific anatomic sites supports the dual morphological subdivision that distinguishes poorly differentiated NECs from well-differentiated NETs. […] Although they can have overlapping histologic features, their inclusion together in a single classification framework may incorrectly lead to the presumption that well-differentiated NETs and poorly differentiated NECs are closely related neoplasms; in most organs where these families of neoplasms have been studied, the data suggest that they are not biologically closely related. […] In addition, to have different degrees of biological aggressiveness, and different responses to medical therapy, NETs and NECs have different risk factors, hereditary predispositions, relationships to non-NE neoplasia, and underpinning genetics.
#13 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
From a genetic standpoint, NECs have inactivation of RB1 and TP53 that, in contrast, occur rarely in NETs. […] Hereditary NET syndromes present in common patterns, where mainly two pathways are involved: the regulation of the cyclin-dependent cell cycle (especially in MEN1 and MEN4) and the involvement of the PI3K/mTOR pathway. […] The development of newer and evolving treatment options based on an improved understanding at their molecular level, including mTOR, VEGF and PRRT, adds to evidence supporting the further possibility of in-depth study and identification of more treatment options beyond the complete resection for these tumors.
#14 Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches – PubMed
https://pubmed.ncbi.nlm.nih.gov/23459719/
The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. […] Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. […] These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.
#15
http://www.diva-portal.org/smash/record.jsf?pid=diva2:624139
The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. […] Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.
#16 Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation
https://www.mdpi.com/1422-0067/25/2/1331
Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. […] The pathogenesis of PNETs is intricate and characterized by complex interactions among numerous signaling pathways. Each pathway plays a role in different facets of tumor development, encompassing cell proliferation, survival, migration, and angiogenesis. Together, these pathways constitute a complex network that, when disrupted, can result in uncontrolled tumor growth and metastasis. […] While somatic and germline mutations remain of great significance for diagnosis and therapeutic treatment, emerging evidence highlights the pivotal role of epigenetic modifications in shaping the intricate landscape of PNET-related signaling. […] Epigenetic alterations can lead to aberrant gene expression patterns, contributing to uncontrolled cell growth, evasion of cell death, and increased metastatic potentialâthe hallmark characteristics of cancer.
#17 Neuroendocrine Tumors – AADI Bioscience
https://www.aadibio.com/neuroendocrine-tumors/
Neuroendocrine tumors (NETs) are a group of rare and heterogeneous malignancies, most commonly arise from neuroendocrine cells of the gastrointestinal tract (particularly pancreas and small bowel), followed by lung, liver, and thymus. […] The PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs and clinical studies demonstrated safety and efficacy of mTOR inhibitors in patients with NET.
#18 Epidemiology, Pathogenesis, and Prognosis of Pancreatic Neuroendocrine Tumors | SpringerLink
https://link.springer.com/10.1007/978-3-030-41683-6_36
Pancreatic neuroendocrine tumors (NETs) account for 7% of pancreatic tumors. […] The three most common impaired signaling pathways in pancreatic NETs include the PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway, T53/Rb pathway, and chromatin remodeling pathway. […] Considering mTOR pathway plays a crucial role in pathogenesis of NETs, mTOR inhibitor for management of pancreatic NETs has been shown beneficial.
#19 Neuroendocrine Tumor Pathogenesis and Molecular Testing
https://www.onclive.com/view/neuroendocrine-tumor-pathogenesis-and-molecular-testing
The role of molecular testing in neuroendocrine cancers continues to evolve. […] Unlike other solid tumor malignancies, where the molecular genetics become critically important in terms of treatment, neuroendocrine cancers have not panned out in helping potentially, for example, to find a mutation that can help us drive treatment. The molecular alterations can help us in prognosis. […] We know that there are certain genes that can portend a poorer or more aggressive course, but we haven’t yet translated that piece into the clinic to say that all patients with neuroendocrine cancers should be molecularly tested. […] The tumor microenvironment of neuroendocrine cancers, we’ve actually known for a very long time it really is driven in part by VEGF and blood vessels. […] These neuroendocrine cancers really require that blood vessel nourishment for them to grow and propagate.
#20 Neuroendocrine Tumor Pathogenesis and Molecular Testing
https://www.onclive.com/view/neuroendocrine-tumor-pathogenesis-and-molecular-testing
More recently in the last decade or so there’s been a big push to go even more to a micro level to use VEGF inhibitors to again impair that angiogenesis and prevent the cancers from growing and spreading. […] There are lots of opportunities with different types of VEGF inhibitors to inhibit the cancer through antiproliferative effects, focusing on that microenvironment with angiogenesis playing an important role.
#21 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The research performed in SI-NETs on three well-known pathways (Hedgehog, Notch and Wnt), which are all implicated both in fibrotic diseases and cancer, will be discussed below. […] The role of Hedgehog signalling in the development of MF is still undetermined. […] The role of ASCL1 in tumourigenesis is complex and not well studied, but in transfected BON1 cells, Notch signalling mediated loss of ASCL1 and decreased serotonin production. […] The findings on Notch signalling in SI-NETs in vivo are conflicting. […] These findings suggest a minor role for Wnt/-catenin signalling in SI-NET development and fibrosis. […] In order to elucidate potential new roads for scientific research and therapies to improve the management of MF, we first discussed the pathobiology of MF. […] A deregulation of the cellular processes in the TME is at the core of fibrosis development. […] Therefore, we discussed possible alternatives for patients with SI-NETs suffering from the complications of MF.
#22 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Most pancreatic neuroendocrine tumors occur sporadically (90%). However, they may be part of hereditary syndromes: multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausens disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). […] In these cases, the underling genetic abnormalities play a significant role in the development of PETs which are often found to be mutlifocal. The pathological features of familial/hereditary PETs are generally similar to the sporadic form, although PETs arising in VHL syndrome patients may have clear cell features. […] Germline loss-of-function MEN-1 mutation leads to the formation of numerous microadenomas, mostly resulting in non-functional PETs and insulinomas. NF-1 or TSC1/2 mutations result in loss of function of their protein products neurofibromin and tuberin, respectively. Notably, the intact proteins suppress the function of a common target, namely mTOR (mammalian target of rapamycin).
#23 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Most pancreatic neuroendocrine tumors occur sporadically (90%). However, they may be part of hereditary syndromes: multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausens disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). […] In these cases, the underling genetic abnormalities play a significant role in the development of PETs which are often found to be mutlifocal. The pathological features of familial/hereditary PETs are generally similar to the sporadic form, although PETs arising in VHL syndrome patients may have clear cell features. […] Germline loss-of-function MEN-1 mutation leads to the formation of numerous microadenomas, mostly resulting in non-functional PETs and insulinomas. NF-1 or TSC1/2 mutations result in loss of function of their protein products neurofibromin and tuberin, respectively. Notably, the intact proteins suppress the function of a common target, namely mTOR (mammalian target of rapamycin).
#24 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Most pancreatic neuroendocrine tumors occur sporadically (90%). However, they may be part of hereditary syndromes: multiple endocrine neoplasia type 1 (MEN1 syndrome), von Hippel-Lindau disease (VHL), von Recklinghausens disease or neurofibromatosis type 1 (NF-1), and tuberous sclerosis (TSC). […] In these cases, the underling genetic abnormalities play a significant role in the development of PETs which are often found to be mutlifocal. The pathological features of familial/hereditary PETs are generally similar to the sporadic form, although PETs arising in VHL syndrome patients may have clear cell features. […] Germline loss-of-function MEN-1 mutation leads to the formation of numerous microadenomas, mostly resulting in non-functional PETs and insulinomas. NF-1 or TSC1/2 mutations result in loss of function of their protein products neurofibromin and tuberin, respectively. Notably, the intact proteins suppress the function of a common target, namely mTOR (mammalian target of rapamycin).
#25 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Furthermore, hypoxia-induced factor (HIF)-dependent mTOR activation links disturbed mTOR signaling to VHL disease. mTOR is a key regulator of cell growth and integrates a wide variety of cellular inputs, such as growth factors, nutrients, energy status and hypoxia-induced stress, thus, it is a good therapeutic target for PETs. […] Sporadic endocrine pancreatic tumors: molecular genetics and pathobiology genome-wide analyses by comparative genomic hybridization (CGH) indicate that the chromosomal losses occur slightly more frequently than gains, whereas amplifications are uncommon. Losses of chromosome 1 and 11q as well as gains of 9q appear to be early events in the development of pancreatic tumors. […] These findings point towards a tumor suppressor pathway and chromosomal instability as important mechanisms associated with malignancy in pancreatic endocrine tumors.
#26 Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms – UpToDate
https://www.uptodate.com/contents/pathology-classification-and-grading-of-neuroendocrine-neoplasms-arising-in-the-digestive-system
Neuroendocrine neoplasms (NENs), defined as epithelial neoplasms with predominant neuroendocrine differentiation, can arise in most organs. […] Gastroenteropancreatic (GEP) NENs arise from either the tubular gastrointestinal tract or the pancreas. […] The classification and nomenclature of NENs is complex, and there is no one single system that is suitable for all NENs, independent of the primary tumor site. […] A common framework for the classification of NENs has been proposed by the World Health Organization (WHO). […] GEP NENs are classified by tumor differentiation status and tumor grade. […] The terminology of GEP NENs has evolved to reflect a separation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). […] Although gastrointestinal NETs and pancreatic NETs may have similar characteristics on routine histologic evaluation, they have a different pathogenesis and biology.
#27 The Nature of Neuroendocrine Tumors
https://www.onclive.com/view/the-nature-of-neuroendocrine-tumors
Neuroendocrine tumors are actually a very broad category of malignancies. […] Molecular testing is an interesting topic in neuroendocrine tumors. […] Not a lot is known about the microenvironment. That is an active area of research and a very important, I would say, area of research in neuroendocrine tumors right now. The aggressive neuroendocrine tumors do appear to be responsive to checkpoint inhibitors, suggesting that the environment is not particularly immunosuppressive. […] A big question right now is can you change that, and can you potentially make these low-grade neuroendocrine tumors responsive to immunotherapy?
#28 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The local microenvironment of cancer cells is commonly referred to as reactive stroma. […] The TME is crucial for tumour growth, invasion and metastasis, with both cancer-promoting as cancer-restraining actions of most components and is known to differ between cancer types. […] The tumour stroma of SI-NETs differs from other cancers with a characteristic desmoplastic reaction and limited leukocytic infiltration. […] Therefore, the pathobiological processes in the SI-NET TME differ from other cancer types. […] This activated phenotype of cancer-associated fibroblasts (CAFs) is identified by expression of -smooth muscle actin (SMA). […] This suggests that also in SI-NETs, CAFs are important regulators of fibrotic stromal programmes. […] A major component of the leukocytic infiltrate in the TME is the tumour-associated macrophages (TAMs).
#29 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The local microenvironment of cancer cells is commonly referred to as reactive stroma. […] The TME is crucial for tumour growth, invasion and metastasis, with both cancer-promoting as cancer-restraining actions of most components and is known to differ between cancer types. […] The tumour stroma of SI-NETs differs from other cancers with a characteristic desmoplastic reaction and limited leukocytic infiltration. […] Therefore, the pathobiological processes in the SI-NET TME differ from other cancer types. […] This activated phenotype of cancer-associated fibroblasts (CAFs) is identified by expression of -smooth muscle actin (SMA). […] This suggests that also in SI-NETs, CAFs are important regulators of fibrotic stromal programmes. […] A major component of the leukocytic infiltrate in the TME is the tumour-associated macrophages (TAMs).
#30 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
TAMs have in general a tumour-promoting role, suppress the adaptive immune system and stimulate fibrosis by secretion of profibrotic factors such as TGF. […] The final component of the TME to be discussed is the extracellular matrix (ECM). […] As the EC cell and BON1 cells, a pancreatic NET cell line, are mechanosensitive and mechanical stress has been shown to induce release of signalling molecules such as serotonin in these cells, changes in ECM composition might influence tumour functionality in SI-NETs by biochemical and biomechanical signals. […] As mentioned earlier, deregulation of signals changes the microenvironment resulting in tumour progression and fibrosis. […] In this next part, growth factors with known profibrotic effects will be discussed, in order to further elucidate the pathobiology of fibrosis in SI-NETs.
#31 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The local microenvironment of cancer cells is commonly referred to as reactive stroma. […] The TME is crucial for tumour growth, invasion and metastasis, with both cancer-promoting as cancer-restraining actions of most components and is known to differ between cancer types. […] The tumour stroma of SI-NETs differs from other cancers with a characteristic desmoplastic reaction and limited leukocytic infiltration. […] Therefore, the pathobiological processes in the SI-NET TME differ from other cancer types. […] This activated phenotype of cancer-associated fibroblasts (CAFs) is identified by expression of -smooth muscle actin (SMA). […] This suggests that also in SI-NETs, CAFs are important regulators of fibrotic stromal programmes. […] A major component of the leukocytic infiltrate in the TME is the tumour-associated macrophages (TAMs).
#32 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
TAMs have in general a tumour-promoting role, suppress the adaptive immune system and stimulate fibrosis by secretion of profibrotic factors such as TGF. […] The final component of the TME to be discussed is the extracellular matrix (ECM). […] As the EC cell and BON1 cells, a pancreatic NET cell line, are mechanosensitive and mechanical stress has been shown to induce release of signalling molecules such as serotonin in these cells, changes in ECM composition might influence tumour functionality in SI-NETs by biochemical and biomechanical signals. […] As mentioned earlier, deregulation of signals changes the microenvironment resulting in tumour progression and fibrosis. […] In this next part, growth factors with known profibrotic effects will be discussed, in order to further elucidate the pathobiology of fibrosis in SI-NETs.
#33 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
TAMs have in general a tumour-promoting role, suppress the adaptive immune system and stimulate fibrosis by secretion of profibrotic factors such as TGF. […] The final component of the TME to be discussed is the extracellular matrix (ECM). […] As the EC cell and BON1 cells, a pancreatic NET cell line, are mechanosensitive and mechanical stress has been shown to induce release of signalling molecules such as serotonin in these cells, changes in ECM composition might influence tumour functionality in SI-NETs by biochemical and biomechanical signals. […] As mentioned earlier, deregulation of signals changes the microenvironment resulting in tumour progression and fibrosis. […] In this next part, growth factors with known profibrotic effects will be discussed, in order to further elucidate the pathobiology of fibrosis in SI-NETs.
#34 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
TAMs have in general a tumour-promoting role, suppress the adaptive immune system and stimulate fibrosis by secretion of profibrotic factors such as TGF. […] The final component of the TME to be discussed is the extracellular matrix (ECM). […] As the EC cell and BON1 cells, a pancreatic NET cell line, are mechanosensitive and mechanical stress has been shown to induce release of signalling molecules such as serotonin in these cells, changes in ECM composition might influence tumour functionality in SI-NETs by biochemical and biomechanical signals. […] As mentioned earlier, deregulation of signals changes the microenvironment resulting in tumour progression and fibrosis. […] In this next part, growth factors with known profibrotic effects will be discussed, in order to further elucidate the pathobiology of fibrosis in SI-NETs.
#35 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
Serotonin is a biogenic amine that can act as a neurotransmitter, hormone or growth factor. […] The ability of serotonin to have a wide array of effects is attributed to its diverse receptor system. […] A causal link between serotonin and fibrosis is furthermore suggested by the association of fibrotic complications with drugs targeting 5-HT2B receptor such as methysergide, an anti-migraine drug. […] The TGF family of cytokines is a pivotal regulator of proliferative and profibrotic processes. […] TGF signalling has a dual role with on the one hand antitumourigenic and antiproliferative effects in physiological and early neoplastic conditions, and on the other hand, protumourigenic effects such as proliferation and invasion in later stages of malignant disease. […] Due to its profibrotic and protumourigenic effects, TGF is one of the most extensively studied growth factors in SI-NETs.
#36 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The expression of TGF isoforms differs between tissue components with all three isoforms being present in tumour tissue, but only TGF2 showed strong IHC staining in stroma. […] PDGF has a strong proliferative effect on fibroblasts and can induce proliferation of epithelial cancer cells. […] The profibrotic effects of PDGF are mediated by binding to the PDGF – and -receptors. […] FGF2 is an important regulator of wound healing and is known to have a strong mitogenic effect on fibroblasts. […] TGF and epidermal growth factor (EGF) are both ligands of EGFR, a receptor tyrosine kinase. […] CTGF is a member of the CCN family of growth factors, which are induced by cytokines such as TGF and importantly also by serotonin. […] However, their effects on fibrosis and MF are much less well studied.
#37 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
Serotonin is a biogenic amine that can act as a neurotransmitter, hormone or growth factor. […] The ability of serotonin to have a wide array of effects is attributed to its diverse receptor system. […] A causal link between serotonin and fibrosis is furthermore suggested by the association of fibrotic complications with drugs targeting 5-HT2B receptor such as methysergide, an anti-migraine drug. […] The TGF family of cytokines is a pivotal regulator of proliferative and profibrotic processes. […] TGF signalling has a dual role with on the one hand antitumourigenic and antiproliferative effects in physiological and early neoplastic conditions, and on the other hand, protumourigenic effects such as proliferation and invasion in later stages of malignant disease. […] Due to its profibrotic and protumourigenic effects, TGF is one of the most extensively studied growth factors in SI-NETs.
#38 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
Serotonin is a biogenic amine that can act as a neurotransmitter, hormone or growth factor. […] The ability of serotonin to have a wide array of effects is attributed to its diverse receptor system. […] A causal link between serotonin and fibrosis is furthermore suggested by the association of fibrotic complications with drugs targeting 5-HT2B receptor such as methysergide, an anti-migraine drug. […] The TGF family of cytokines is a pivotal regulator of proliferative and profibrotic processes. […] TGF signalling has a dual role with on the one hand antitumourigenic and antiproliferative effects in physiological and early neoplastic conditions, and on the other hand, protumourigenic effects such as proliferation and invasion in later stages of malignant disease. […] Due to its profibrotic and protumourigenic effects, TGF is one of the most extensively studied growth factors in SI-NETs.
#39 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The expression of TGF isoforms differs between tissue components with all three isoforms being present in tumour tissue, but only TGF2 showed strong IHC staining in stroma. […] PDGF has a strong proliferative effect on fibroblasts and can induce proliferation of epithelial cancer cells. […] The profibrotic effects of PDGF are mediated by binding to the PDGF – and -receptors. […] FGF2 is an important regulator of wound healing and is known to have a strong mitogenic effect on fibroblasts. […] TGF and epidermal growth factor (EGF) are both ligands of EGFR, a receptor tyrosine kinase. […] CTGF is a member of the CCN family of growth factors, which are induced by cytokines such as TGF and importantly also by serotonin. […] However, their effects on fibrosis and MF are much less well studied.
#40 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The expression of TGF isoforms differs between tissue components with all three isoforms being present in tumour tissue, but only TGF2 showed strong IHC staining in stroma. […] PDGF has a strong proliferative effect on fibroblasts and can induce proliferation of epithelial cancer cells. […] The profibrotic effects of PDGF are mediated by binding to the PDGF – and -receptors. […] FGF2 is an important regulator of wound healing and is known to have a strong mitogenic effect on fibroblasts. […] TGF and epidermal growth factor (EGF) are both ligands of EGFR, a receptor tyrosine kinase. […] CTGF is a member of the CCN family of growth factors, which are induced by cytokines such as TGF and importantly also by serotonin. […] However, their effects on fibrosis and MF are much less well studied.
#41 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The expression of TGF isoforms differs between tissue components with all three isoforms being present in tumour tissue, but only TGF2 showed strong IHC staining in stroma. […] PDGF has a strong proliferative effect on fibroblasts and can induce proliferation of epithelial cancer cells. […] The profibrotic effects of PDGF are mediated by binding to the PDGF – and -receptors. […] FGF2 is an important regulator of wound healing and is known to have a strong mitogenic effect on fibroblasts. […] TGF and epidermal growth factor (EGF) are both ligands of EGFR, a receptor tyrosine kinase. […] CTGF is a member of the CCN family of growth factors, which are induced by cytokines such as TGF and importantly also by serotonin. […] However, their effects on fibrosis and MF are much less well studied.
#42 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
The expression of TGF isoforms differs between tissue components with all three isoforms being present in tumour tissue, but only TGF2 showed strong IHC staining in stroma. […] PDGF has a strong proliferative effect on fibroblasts and can induce proliferation of epithelial cancer cells. […] The profibrotic effects of PDGF are mediated by binding to the PDGF – and -receptors. […] FGF2 is an important regulator of wound healing and is known to have a strong mitogenic effect on fibroblasts. […] TGF and epidermal growth factor (EGF) are both ligands of EGFR, a receptor tyrosine kinase. […] CTGF is a member of the CCN family of growth factors, which are induced by cytokines such as TGF and importantly also by serotonin. […] However, their effects on fibrosis and MF are much less well studied.
#43
https://neoplasiaresearch.com/pms/index.php/jcru/article/view/563
Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of neoplasms that are the second most common among pancreatic neoplasms. […] Therefore, treatment with drugs targeting PNET oncogenesis is a promising strategy in such patients. In this work, we review the present knowledge on the molecular nature of PNETs, and the genetic basis of PNET-associated hereditary syndromes, including multiple endocrine neoplasia type I, von Hippel-Lindau disease, neurofibromatosis type I, and tuberous sclerosis. […] Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. […] Schmitt AM, Schmid S, Rudolph T, et al. VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. […] Briest F, Grabowski P. PI3K-AKT-mTOR-signaling and beyond: the complex network in gastroenteropancreatic neuroendocrine neoplasms.
#44 Pancreatic neuroendocrine tumor – Wikipedia
https://en.wikipedia.org/wiki/Pancreatic_neuroendocrine_tumor
PanNETs are a type of neuroendocrine tumor, representing about one-third of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). […] Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four important findings: […] the genes mutated in NETs, MEN1, ATRX, DAXX, TSC2, PTEN and PIK3CA, are different from the mutated genes previously found in pancreatic adenocarcinoma. […] mutations affecting a new cancer pathway involving ATRX and DAXX genes were found in about 40% of pancreatic NETs. […] ATRX/DAXX and MEN1 mutations were associated with a better prognosis.
#45 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Furthermore, hypoxia-induced factor (HIF)-dependent mTOR activation links disturbed mTOR signaling to VHL disease. mTOR is a key regulator of cell growth and integrates a wide variety of cellular inputs, such as growth factors, nutrients, energy status and hypoxia-induced stress, thus, it is a good therapeutic target for PETs. […] Sporadic endocrine pancreatic tumors: molecular genetics and pathobiology genome-wide analyses by comparative genomic hybridization (CGH) indicate that the chromosomal losses occur slightly more frequently than gains, whereas amplifications are uncommon. Losses of chromosome 1 and 11q as well as gains of 9q appear to be early events in the development of pancreatic tumors. […] These findings point towards a tumor suppressor pathway and chromosomal instability as important mechanisms associated with malignancy in pancreatic endocrine tumors.
#46 Molecular pathology of pancreatic neuroendocrine tumors – Chen – Journal of Gastrointestinal Oncology
https://jgo.amegroups.org/article/view/416/html
Recent studies using genome-wide single nucleotide polymorphism (SNP) analysis showed that about 30-40% of pancreatic endocrine tumors had high genetic imbalances defined by chromosomal aberrations. […] The data suggest that multiple genetic defects may accumulate and result in PETs progression and malignancy. Molecular genetic tests are relevant to the pathogenesis, however, these tests are currently not useful in the diagnostic process. […] The epigenetic modifications and differential microRNA-expression mechanistically involved in the dysregulated signaling pathways of PETs are under further investigation.
#47 Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation
https://www.mdpi.com/1422-0067/25/2/1331
Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. […] The pathogenesis of PNETs is intricate and characterized by complex interactions among numerous signaling pathways. Each pathway plays a role in different facets of tumor development, encompassing cell proliferation, survival, migration, and angiogenesis. Together, these pathways constitute a complex network that, when disrupted, can result in uncontrolled tumor growth and metastasis. […] While somatic and germline mutations remain of great significance for diagnosis and therapeutic treatment, emerging evidence highlights the pivotal role of epigenetic modifications in shaping the intricate landscape of PNET-related signaling. […] Epigenetic alterations can lead to aberrant gene expression patterns, contributing to uncontrolled cell growth, evasion of cell death, and increased metastatic potentialâthe hallmark characteristics of cancer.
#48 Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation
https://www.mdpi.com/1422-0067/25/2/1331
The contributions of these epigenetic modifications to PNET pathology have yet to be fully explored. […] The unique slowing growth characteristic of PNETs also presents a practical challenge for research work in laboratories. […] Despite the inherent challenges, some encouraging advancements have been achieved. Notably, recognizing the limited effectiveness of epigenetic cancer drugs has prompted investigations into combining these therapies with existing or emerging targeted treatments for a synergistic and combinatorial approach. […] The ongoing exploration of the specific mechanisms governing epigenetic changes in PNETs, alongside innovative strategies for drug development, holds considerable promise for enhancing the prognosis and quality of life for individuals grappling with this challenging malignancy.
#49 Research advances in the mechanism of tumor microenvironment and targeted therapy for pancreatic neuroendocrine tumor
https://lcgdbzz.com/en/article/doi/10.3969/j.issn.1001-5256.2023.08.036
The tumor microenvironment of pancreatic neuroendocrine tumor is a tumor-promoting microenvironment composed of tumor cells, immune/immunosuppressive cells, and extracellular matrix and has the marked feature of immunosuppression. […] It can lead to the immune escape, invasion, and metastasis of tumor cells by inhibiting antitumor immune response and promoting angiogenesis and is also the main cause of drug resistance to antitumor treatment. […] Therefore, it is of great significance to design new therapeutic strategies from the perspective of the tumor microenvironment of pancreatic neuroendocrine tumor to reverse suppressive tumor microenvironment and improve the treatment outcome of pancreatic neuroendocrine tumor. […] This article reviews the latest research advances in the composition and role of the tumor microenvironment of pancreatic neuroendocrine tumor and related targeted therapy.
#50
https://insight.jci.org/articles/view/160130
Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. […] We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. […] RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. […] We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. […] T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. […] A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs.
#51
https://insight.jci.org/articles/view/160130
Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. […] Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs. […] To investigate early changes accompanying disease progression to metastasis, we performed RNA-Seq analysis on surgically excised primary tumors originating from both localized and metastatic PNETs. […] We aimed to determine whether unique molecular signatures distinguished metastatic PNETs from localized tumors in the primary tumor site in the pancreas. […] This information was then used to define characteristics associated with tumor and immune cell interaction, depending upon the metastatic potential, followed by a comprehensive analysis of patients tumor tissues using IHC and flow cytometry.
#52 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. […] As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.
#53 Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum in: Endocrine-Related Cancer Volume 25 Issue 3 (2018)
https://erc.bioscientifica.com/view/journals/erc/25/3/ERC-17-0380.xml
Another hallmark of SI-NETs is the ability to induce fibrosis. The fibrosis can occur around the tumour or at distant sites. […] However, in this review, we will focus on local fibrotic complications, of which mesenteric fibrosis (MF) is most notable and occurs in up to 50% of SI-NET patients. […] Because survival of patients improved since the development of targeted and more effective therapies for carcinoid syndrome and tumour growth control, there is increased need for advancements in treatment options for MF. […] As improved knowledge of the pathogenesis of fibrosis is key to the development of new therapies, we assessed in this review literature on putative mediators of MF in SI-NETs and treatments targeting these factors. […] Understanding the TME is crucial in order to decipher how SI-NETs induce fibrosis.
#54 Martyn Caplin NETRF Research Project
https://netrf.org/research/mesenteric-fibrosis-in-small-intestinal-neuroendocrine-tumors-pathogenesis/
Caplin will lead a collaborative project between two leading European Neuroendocrine Tumor Society Centers of Excellence â The Royal Free-UCL London and Erasmus University Medical Center, Rotterdam â to explore the underlying molecular cause of mesenteric fibrosis. […] Our research program will investigate the factors and pathways involved in the development of small intestinal neuroendocrine tumor (SI-NET) mesenteric fibrosis (MF). […] We will study the interactions between SI-NET cells and cancer-associated fibroblasts (cells making fibrosis factors) and assess the modulating effects of sex steroids on fibrogenesis. This research will provide insight into the cause of MF and could result in the development of (predictive) biomarkers for MF as well as the identification of new therapeutic targets to inhibit cell growth and development of fibrosis.
#55 Martyn Caplin NETRF Research Project
https://netrf.org/research/mesenteric-fibrosis-in-small-intestinal-neuroendocrine-tumors-pathogenesis/
Caplin will lead a collaborative project between two leading European Neuroendocrine Tumor Society Centers of Excellence â The Royal Free-UCL London and Erasmus University Medical Center, Rotterdam â to explore the underlying molecular cause of mesenteric fibrosis. […] Our research program will investigate the factors and pathways involved in the development of small intestinal neuroendocrine tumor (SI-NET) mesenteric fibrosis (MF). […] We will study the interactions between SI-NET cells and cancer-associated fibroblasts (cells making fibrosis factors) and assess the modulating effects of sex steroids on fibrogenesis. This research will provide insight into the cause of MF and could result in the development of (predictive) biomarkers for MF as well as the identification of new therapeutic targets to inhibit cell growth and development of fibrosis.
#56 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
Neuroendocrine neoplasms (NENs) are a group of heterogeneous tumors with neuroendocrine differentiation that can arise from any organ. […] A significant proportion of NEN patients experience endocrine imbalances consequent to increased amine or peptide hormone secretion, impacting their quality of life and prognosis. […] Over the last decade, pathologic categorization, diagnostic techniques and therapeutic choices for NENs both well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) have appreciably evolved. […] Therapy for NENs has progressed recently based on a better molecular understanding, including the involvement of mTOR, VEGF and peptide receptor radionuclide therapy (PRRT), which add to the growing evidence supporting the possibility of treatment beyond complete resection.
#57 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://pmc.ncbi.nlm.nih.gov/articles/PMC10420169/
From a genetic standpoint, NECs have inactivation of RB1 and TP53 that, in contrast, occur rarely in NETs. […] Hereditary NET syndromes present in common patterns, where mainly two pathways are involved: the regulation of the cyclin-dependent cell cycle (especially in MEN1 and MEN4) and the involvement of the PI3K/mTOR pathway. […] The development of newer and evolving treatment options based on an improved understanding at their molecular level, including mTOR, VEGF and PRRT, adds to evidence supporting the further possibility of in-depth study and identification of more treatment options beyond the complete resection for these tumors.
#58 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
The current systemic therapy for NENs mainly targets tumor proliferation and hormone production. The extensive research in this domain has allowed the identification of various drug targets that have been exploited using currently approved and under-trial molecules. […] The development of newer and evolving treatment options based on an improved understanding at their molecular level, including mTOR, VEGF and PRRT, adds to evidence supporting the further possibility of in-depth study and identification of more treatment options beyond the complete resection for these tumors.
#59 A Comprehensive Review on Neuroendocrine Neoplasms: Presentation, Pathophysiology and Management
https://www.mdpi.com/2077-0383/12/15/5138
The current systemic therapy for NENs mainly targets tumor proliferation and hormone production. The extensive research in this domain has allowed the identification of various drug targets that have been exploited using currently approved and under-trial molecules. […] The development of newer and evolving treatment options based on an improved understanding at their molecular level, including mTOR, VEGF and PRRT, adds to evidence supporting the further possibility of in-depth study and identification of more treatment options beyond the complete resection for these tumors.
#60 Pancreatic Neuroendocrine Tumors (Islet Cell) | Memorial Sloan Kettering Cancer Center
https://www.mskcc.org/cancer-care/types/gastrointestinal-neuroendocrine/pancreatic-neuroendocrine-islet-cell-tumors
Treatment of pancreatic neuroendocrine tumors may include a combination of surgery, hormone therapy, radiation therapy, and chemotherapy. […] Researchers at Memorial Sloan Kettering are exploring new treatment approaches using a mouse model that exhibits pancreatic neuroendocrine tumors. This model will be used to conduct early-stage testing of new drug therapies and targeted antibody-based treatments. The pancreatic neuroendocrine tumor model also will be used to test a new class of drugs that may have the potential to block the production of a protein called cathepsin proteases, which are thought to promote the growth of pancreatic neuroendocrine tumors.
#61 Biomarkers in the Pathogenesis of Neuroendocrine Tumours – Neuroendocrine Cancer UK
https://www.neuroendocrinecancer.org.uk/biomarkers-in-the-pathogenesis-of-neuroendocrine-tumours/
The project built on previous work conducted in Prof Meyers Lab which demonstrated, for the first time, that circulating tumour cells (CTCs) were detectable in the blood of patients with a range of NENs, and that their presence indicated an adverse prognosis. […] Advances in technology now allow for detailed molecular characterisation to be conducted on single cells and the project compared the genetic changes seen in primary tumour tissue with that of CTCs and also with cfDNA (pieces of DNA that arise from the tumour and can be found circulating in the blood stream). […] If we can show that CTCs and cfDNA does indeed accurately represent the tumour, then we will be able to track how the tumour evolves over time and during treatment. This may allow clinicians treating patients with NENs to select the appropriate therapy and to anticipate the emergence of resistance. […] He remains actively involved in clinical and basic science research with his main interests being circulating tumour cells in NENs, mechanisms of mesenteric fibrosis and endoscopic management of NENs.
#62 Biomarkers in the Pathogenesis of Neuroendocrine Tumours – Neuroendocrine Cancer UK
https://www.neuroendocrinecancer.org.uk/biomarkers-in-the-pathogenesis-of-neuroendocrine-tumours/
The project built on previous work conducted in Prof Meyers Lab which demonstrated, for the first time, that circulating tumour cells (CTCs) were detectable in the blood of patients with a range of NENs, and that their presence indicated an adverse prognosis. […] Advances in technology now allow for detailed molecular characterisation to be conducted on single cells and the project compared the genetic changes seen in primary tumour tissue with that of CTCs and also with cfDNA (pieces of DNA that arise from the tumour and can be found circulating in the blood stream). […] If we can show that CTCs and cfDNA does indeed accurately represent the tumour, then we will be able to track how the tumour evolves over time and during treatment. This may allow clinicians treating patients with NENs to select the appropriate therapy and to anticipate the emergence of resistance. […] He remains actively involved in clinical and basic science research with his main interests being circulating tumour cells in NENs, mechanisms of mesenteric fibrosis and endoscopic management of NENs.
#63 Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway | Modern Pathology
https://www.nature.com/articles/modpathol2012143
Our study reveals the preferential expression of NOTCH1 and its downstream effectors, HES1 and HEY1, in rectal neuroendocrine tumors and a subset of pancreatic neuroendocrine tumors. […] Our results confirm the heterogeneity in signaling pathways of gastrointestinal neuroendocrine tumors. […] This study underscores the need for a site-based critical assessment of signaling pathways, when designing clinical trials for gastrointestinal neuroendocrine tumors.
#64 Antiangiogenic Therapy in Pancreatic Neuroendocrine Tumors | Anticancer Research
https://ar.iiarjournals.org/content/36/10/5025
Sunitinib malate is a multi-target agent able to inhibit irreversibly many tyrosine kinases overexpressed in pNETs, including VEGF receptor 2 and 3, PDGFR and stem-cell factor receptor, showing strong antitumor properties. […] The optimization of angiogenic therapy in pNETs is an open question; in particular, a clear clinical end-point has not been identified for bevacizumab therapy in this oncologic setting, as well as the complete spectrum of adverse events associated with its use. […] Basic research, aimed to clarify mechanisms of resistance and find markers of response, is necessary in the near future for designing more appropriate and personalized clinical trials.