Guz mózgu
Patofizjologia i mechanizm
Guzy mózgu, zarówno złośliwe, jak i łagodne, powstają w wyniku mutacji genetycznych zaburzających regulację cyklu komórkowego, co prowadzi do niekontrolowanego wzrostu komórek i tworzenia masy nowotworowej. Kluczowe mutacje dotyczą szlaków sygnałowych MAPK, FGFR, PI3K/AKT/mTOR, Wnt, SHH oraz regulatorów cyklu komórkowego RB i p53. Glejaki wielopostaciowe (GBM), najczęstsze i najbardziej agresywne pierwotne guzy mózgu u dorosłych, charakteryzują się złożonym profilem molekularnym z mutacjami p53 (w około 87% przypadków) i IDH1/2, które wpływają na proliferację, inwazję i oporność na leczenie. Patogeneza obejmuje także zaburzenia mikrośrodowiska guza, angiogenezę indukowaną przez VEGFR oraz mechanizmy immunosupresyjne, co utrudnia skuteczne leczenie. Wtórne guzy mózgu, będące przerzutami z innych narządów (płuca, piersi, czerniak, nerki, przewód pokarmowy), są u dorosłych znacznie częstsze niż guzy pierwotne.
- Patogeneza guza mózgu
- Mechanizmy molekularne powstawania guza mózgu
- Kluczowe szlaki sygnałowe w patogenezie guza mózgu
- Rola kluczowych genów w patogenezie guza mózgu
- Różnice między pierwotnym i wtórnym guzem mózgu
- Mechanizmy wzrostu i inwazji guza mózgu
- Angiogeneza i jej rola w rozwoju guza mózgu
- Wzrost ciśnienia wewnątrzczaszkowego i jego konsekwencje
- Infiltracja i rozprzestrzenianie się guza w mózgu
- Rola komórkowej sygnalizacji w patogenezie guza mózgu
- Rola neuroprzekaźników i środowiska peritumorowego w guzach mózgu
- Mechanizmy oporności na leczenie w guzach mózgu
- Rola komórek macierzystych nowotworów
- Mechanizmy oporności metabolicznej
- Rola kanałów jonowych w oporności guzów mózgu
- Rola autofagii w progresji guza mózgu
- Podsumowanie czynników ryzyka i implikacji klinicznych
Patogeneza guza mózgu
Guz mózgu (znany również jako rak mózgu) powstaje, gdy grupa komórek w mózgu lub w jego okolicy ulega nieprawidłowym zmianom i zaczyna niekontrolowanie rosnąć, tworząc masę. Rozróżniamy dwa główne rodzaje guzów: złośliwe (nowotworowe) i łagodne (nienowotworowe). Bez względu na klasyfikację, wszystkie guzy mózgu mogą potencjalnie zagrażać życiu ze względu na ograniczoną przestrzeń czaszki, w której rozwijają się12.
Mechanizmy molekularne powstawania guza mózgu
Guzy mózgu powstają w wyniku zmian w DNA komórek mózgowych, które powodują zakłócenie normalnych mechanizmów kontrolujących cykl komórkowy. Uszkodzone geny, które w normalnych warunkach regulują tempo podziału komórek, naprawiają defekty innych genów lub inicjują samozniszczenie komórki, gdy uszkodzenie jest zbyt rozległe, przestają właściwie funkcjonować12.
Zmiany genetyczne powodują, że komórki mózgowe otrzymują nowe instrukcje. Dzielą się one szybciej niż zdrowe komórki i żyją dłużej, co prowadzi do nagromadzenia zbyt dużej liczby nieprawidłowo funkcjonujących komórek, które ostatecznie tworzą guz12.
Aktualne badania molekularne wykazały, że w patogenezie guzów mózgu uczestniczą głównie dwie grupy mutacji molekularnych, które dotyczą różnych szlaków regulacji komórkowej:
- Pierwsza podgrupa charakteryzuje się mutacjami w szlaku kinazy aktywowanej mitogenami (MAPK), który uczestniczy we wzroście komórkowym1
- Druga grupa wykazuje mutacje w genach czynnika wzrostu fibroblastów (FGFR), głównie FGFR-1, które znajdują się powyżej szlaku MAPK2
Kluczowe szlaki sygnałowe w patogenezie guza mózgu
Najnowsze zintegrowane badania genomiczne wskazują na udział określonych sieci molekularnych w patogenezie glejaków i rdzeniaków. Do najważniejszych należą szlaki sygnałowe receptorów kinazy tyrozynowej (RTK) działające poprzez szlaki Ras-MAPK i PI3K-AKT-mTOR, sygnalizacja Wnt i sonic hedgehog (SHH), wraz ze szlakami regulującymi cykl komórkowy – RB i p531.
W glejakach wielopostaciowych (GBM), które są najczęstszymi i najbardziej agresywnymi pierwotnymi guzami mózgu u dorosłych, obserwuje się złożony profil molekularny, napędzany przez zaburzenia w wielu szlakach sygnałowych, w tym PI3K/AKT/mTOR, Wnt, NF-κB i TGF-β, które są kluczowe dla wzrostu guza, inwazji i oporności na leczenie12.
Warto podkreślić, że ludzkie złośliwe glejaki, w tym glejaki wielopostaciowe, zazwyczaj nie polegają na pojedynczym onkogenie lub genie supresorowym dla ich inicjacji i progresji. Zamiast tego występowanie wielu zdysregulowanych szlaków sygnałowych w GBM podkreśla ideę, że guzy polegają na zakłóceniu różnych celów molekularnych, które wspólnie wpływają na biologię guza2.
Rola kluczowych genów w patogenezie guza mózgu
Gen p53 koduje białko kluczowe dla regulacji odpowiedzi komórkowych na stres poprzez kontrolowanie ekspresji genów docelowych zaangażowanych w istotne procesy, w tym regulację cyklu komórkowego, apoptozę, różnicowanie, starzenie się, naprawę DNA i neowaskularyzację1. Mutacja p53, często następująca po mutacjach IDH1/2, stanowi kluczowe zdarzenie genetyczne, z wyjątkiem przypadków zespołu Li-Fraumeni1. Szacuje się, że około 87% pacjentów z GBM ma związaną z tym mutację p531.
Szlak białka retinoblastoma (RB) odgrywa kluczową rolę w zatrzymaniu inicjacji i progresji cyklu komórkowego, działając w tandemie ze szlakiem p531. Wysoka częstość występowania mutacji p53 w GBM podkreśla ich potencjał jako kluczowych celów dla terapii medycyny precyzyjnej2.
Istocytryna dehydrogenaza (IDH), składająca się z 3 izoform: IDH1, IDH2 i IDH3, odgrywa kluczową rolę w cyklu Krebsa, ułatwiając konwersję izocytrynianu do α-ketoglutaranu (α-KG)1. Mutacje w genach IDH prowadzą do wytwarzania 2-hydroksyglutaranu (2-HG), który podnosi poziomy białka rybosomalnego S6, odgrywającego rolę w sygnalizacji mTOR2. Mutacje te wpływają na geny supresorowe nowotworów, takie jak fosforanowa i homolog tensyny (PTEN), białko nowotworowe p53 (TP53) i Neurofibromin 1 (NF1)1.
Różnice między pierwotnym i wtórnym guzem mózgu
Guzy pierwotne rozwijają się bezpośrednio z komórek mózgu lub okolicznych tkanek, podczas gdy guzy wtórne (przerzutowe) powstają, gdy nowotwór z innej części ciała rozprzestrzenia się do mózgu1. U dorosłych wtórne guzy mózgu są znacznie częstsze niż guzy pierwotne2.
Pierwotne guzy OUN obejmują wszystkie pierwotne nowotwory zlokalizowane w OUN, osłonkach OUN i początkach nerwów zlokalizowanych w czaszce i kręgosłupie. Wtórne guzy OUN to przerzuty do OUN; wszystkie są złośliwe i mogą być pojedyncze lub mnogie1.
Guzy przerzutowe są najczęstszym typem guza OUN u dorosłych. Źródłami przerzutów do mózgu (w kolejności malejącej) są: nowotwory płuc, piersi, skóry (czerniak), nerek i przewodu pokarmowego2.
Mechanizmy wzrostu i inwazji guza mózgu
Guzy mózgu wywołują objawy neurologiczne poprzez szereg mechanizmów. Małe, krytycznie zlokalizowane guzy mogą uszkodzić określone szlaki nerwowe przechodzące przez mózg. Guzy mogą najeżdżać, infiltrować lub zastępować normalną tkankę miąższową, zakłócając prawidłowe funkcjonowanie1.
Angiogeneza i jej rola w rozwoju guza mózgu
Guzy mogą wytwarzać substancje zwane czynnikami angiogenezy, które promują wzrost naczyń krwionośnych. Nowe naczynia, które powstają, zwiększają dopływ składników odżywczych do guza, a ostatecznie guz staje się zależny od tych nowych naczyń1. Proces ten jest szczególnie istotny w glejakach wielopostaciowych, gdzie szlak sygnałowy receptora czynnika wzrostu śródbłonka naczyniowego (VEGFR) uważany jest za kluczowy czynnik przeżycia guza1.
Nowotwory złośliwe mogą rozwijać nowe wewnętrzne naczynia krwionośne, które mogą krwawić lub ulec okluzji, powodując martwicę i dysfunkcję neurologiczną naśladującą udar1. Te nowo powstałe naczynia zakłócają normalną barierę krew-mózg i promują obrzęk2.
Wzrost ciśnienia wewnątrzczaszkowego i jego konsekwencje
Ponieważ mózg znajduje się w ograniczonej objętości jamy czaszki, wzrost guzów wewnątrzczaszkowych z towarzyszącym obrzękiem może powodować zwiększone ciśnienie wewnątrzczaszkowe. Guzy przylegające do trzeciej i czwartej komory mózgu mogą utrudniać przepływ płynu mózgowo-rdzeniowego, prowadząc do wodogłowia obstrukcyjnego1.
Skumulowane efekty inwazji guza, obrzęku i wodogłowia mogą podnosić ciśnienie wewnątrzczaszkowe (ICP) i zaburzać perfuzję mózgową. Wzrost ICP w przedziale wewnątrzczaszkowym może prowokować przesunięcie lub wklinowanie tkanki pod sierp mózgu, przez namiot móżdżku lub przez otwór wielki2.
Rosnący guz musi rozwijać się kosztem utraty objętości innych składników w jamie czaszki. Dlatego tkanka mózgowa, płyn mózgowo-rdzeniowy i krew w krążeniu mózgowym muszą się cofnąć, aby zrobić dodatkowe miejsce dla zajmującego przestrzeń guza. Ten mechanizm nazywany jest kompensacją i na tym etapie ciśnienie wewnątrzczaszkowe nie jest podwyższone. Gdy mechanizmy kompensacyjne zostają wyczerpane, ciśnienie wewnątrzczaszkowe gwałtownie wzrasta, prowadząc do zagrażających życiu zakłóceń podstawowych funkcji mózgu1.
Infiltracja i rozprzestrzenianie się guza w mózgu
Większość pierwotnych guzów mózgu nie daje przerzutów, ale jeśli to robią, rozprzestrzenianie się wewnątrzczaszkowe zazwyczaj poprzedza rozsiew odległy1. Guzy mózgu mogą powodować problemy bezpośrednio inwazyjnie i niszcząc zdrową tkankę mózgową, wywierając nacisk na pobliskie tkanki, zwiększając ciśnienie wewnątrzczaszkowe, powodując gromadzenie płynu w mózgu, blokując normalny przepływ płynu mózgowo-rdzeniowego (CSF) przez przestrzenie w mózgu, powodując powiększenie tych przestrzeni i prowadząc do krwawienia w mózgu1.
Gwiaździaki rozprzestrzeniają się wzdłuż dróg istoty białej i nie respektują granic płatów. Ze względu na ten infiltrujący wzrost, w wielu przypadkach guz jest faktycznie większy niż można zobrazować za pomocą rezonansu magnetycznego1. Niektóre guzy wykazują rozsiew podpajęczynówkowy i tworzą guzkowate zmiany wzdłuż mózgu i rdzenia kręgowego2.
Glejak wielopostaciowy (GBM) często przekracza linię środkową, infiltrując drogi istoty białej ciała modzelowatego3. Guzy łagodne rosną powoli i mogą osiągnąć znaczne rozmiary przed wywołaniem objawów, częściowo dlatego, że często nie ma obrzęku mózgu. Złośliwe guzy pierwotne rosną szybko, ale rzadko rozprzestrzeniają się poza OUN. Śmierć wynika z lokalnego wzrostu guza i/lub krwawienia związanego z guzem i tym samym może wynikać zarówno z guzów łagodnych, jak i złośliwych2.
Rola komórkowej sygnalizacji w patogenezie guza mózgu
Sygnalizacja komórkowa odgrywa kluczową rolę w rozwoju guzów mózgu. Zrozumienie szlaków sygnałowych, które wpływają na złośliwe zachowanie komórek guza mózgu, może otworzyć drogę do opracowania nowych terapii celowanych1.
Szlak PI3K/AKT/mTOR
Wewnątrzkomórkowy szlak sygnałowy PI3K/AKT/mTOR odgrywa kluczową rolę w regulacji różnych procesów komórkowych, w tym wzrostu, proliferacji i metabolizmu. Dysfunkcja sygnalizacji PI3K/AKT/mTOR jest powszechnie obserwowana w wielu nowotworach, przyczyniając się do nowotworzenia poprzez promowanie niekontrolowanego wzrostu komórek, przeżycia i oporności na apoptozę1.
Kinazy PI3K, rodzina heterodimierycznych kinaz, według doniesień zawierają zmiany genetyczne w 88% przypadków GBM1. Gdy aktywność PTEN (fosfataza i homolog tensyny) zostaje utracona poprzez mutację lub LOH (utratę heterozygotyczności), PIP3 (fosfatydyloinozytolo-3,4,5-trifosforan) akumuluje się i powoduje złośliwy wzrost poprzez konstytutywną aktywację szlaku PI3K/Akt1.
Szlak NF-κB
Trwała i nieprawidłowa aktywacja szlaku sygnałowego NF-κB jest cechą charakterystyczną GBM1. Szlak ten jest zaangażowany w regulację ekspresji genów i odpowiedzi zapalnych, które mogą promować przeżycie komórek nowotworowych i oporność na leczenie.
Szlak Wnt
Szlak sygnałowy Wnt jest starożytnym i fundamentalnym programem genetycznym, który dostarcza kluczowych instrukcji regulacyjnych dla wzrostu komórek, różnicowania i wzoru tkanek2. W glejakach wielopostaciowych ten szlak często ulega deregulacji, przyczyniając się do rozwoju i progresji guza. Sygnalizacja Wnt moduluje samoodnawianie, proliferację i różnicowanie komórek progenitorowych neuronalnych (NPC) w mózgu na różnych etapach rozwoju OUN2.
Szlak TGF-β
Szlak sygnałowy transformującego czynnika wzrostu β (TGF-β) odgrywa kluczową rolę w regulacji kluczowych procesów komórkowych, w tym proliferacji, odpowiedzi immunologicznej, apoptozy i adhezji3. TGF-β2 jest inhibitorem komórek T w mikrośrodowisku guza GBM, który występuje w około 90% komórek guza GBM2.
Najnowsze badania z Vall d’Hebron Institute of Oncology (VHIO) w Barcelonie ujawniły mechanizmy molekularne prowadzące do wysokich poziomów TGF-β u niektórych pacjentów z glejakiem. Badanie wykazało, że TGF-β wywołuje wzrost RNA do transkrypcji TGF-β, co oznacza, że nadal wysyła sygnały, aby dalej zwiększać aktywność w linii produkcyjnej. Po raz pierwszy zidentyfikowano czynnik odpowiedzialny za wydawanie poleceń łańcuchowi produkcyjnemu: CREB (cAMP response element-binding protein), który jest dyrektorem operacyjnym w tym procesie1.
Szlak MAPK
Szlak sygnałowy MAPK (kinaza aktywowana mitogenami) odgrywa kluczową rolę w różnych nowotworach, w tym w GBM, poprzez jego hiperaktywację, która napędza procesy takie jak migracja, proliferacja i przeżycie4. Szlak ten jest szczególnie istotny w glejakach, gdzie stanowi jeden z głównych mechanizmów związanych z progresją guza.
Rola neuroprzekaźników i środowiska peritumorowego w guzach mózgu
Patogeneza guza mózgu obejmuje złożone interakcje między komórkami guza, mikrośrodowiskiem mózgu i barierą krew-mózg (BBB)1. Dokładna patofizjologia epilepsji związanej z guzem mózgu (BTRE) nie jest dobrze scharakteryzowana, jednak uważa się, że jest wieloczynnikowa. Obciążenie guzem, typ, lokalizacja, tempo wzrostu, mikrośrodowisko bariery krew-mózg, zmieniona homeostaza neuroprzekaźników i zmiany w połączeniach szczelinowych to czynniki, które wpływają na BTRE1.
Glutaminian i inne neuroprzekaźniki
Różne badania na zwierzętach i ludzkich tkankach zidentyfikowały glutaminian, kwas γ-aminomasłowy (GABA) i kinazę adenozynową (ADK) jako możliwe czynniki przyczyniające się do epileptogenezy u pacjentów z guzami mózgu. Badania glejaków u zwierząt wykazały, że aktywność drgawkowa powstawała z powodu podwyższonej produkcji glutaminianu, powodując nadpobudliwość wokół obszaru okołoguzowego1.
Naukowcy odkryli mechanizm, za pomocą którego glejak wielopostaciowy (GBM) promuje utratę funkcji lub śmierć neuronów, proces znany jako neurodegeneracja. Badania wykazały, że onkogen (gen mający zdolność wywoływania raka) o nazwie astrocyte elevated gene (AEG)-1 promuje neurodegenerację poprzez zwiększenie toksyczności glutaminianu dla neuronów. Badanie to jest pierwszym tego rodzaju, które dostarcza bezpośredniego mechanistycznego powiązania między GBM, neurodegeneracją i transportem glutaminianu oraz wyjaśnia proces, za pomocą którego GBM, poprzez ekspresję onkogenu AEG-1, może wywoływać śmierć neuronów1.
Mikroglej i stan zapalny
Stan zapalny zawsze odgrywał rolę w epilepsji, czego dowodem jest istnienie drgawek gorączkowych. Wskazuje to na mechanizm, za pomocą którego stan zapalny wywołuje stan nadpobudliwości w tkance mózgowej1.
W stanie zapalnym układu nerwowego mikroglej i astrocyty wydzielają prozapalne cytokiny (PIC), takie jak interleukina 1 beta (IL-1β), czynnik martwicy nowotworów alfa (TNF-α) i interleukina 6 (IL-6), między innymi. Przeciążenie PIC w OUN prowadzi do przerwania bariery krew-mózg (BBB), skutkując dalszym napływem PIC z krążenia systemowego1.
Badacze z The Wistar Institute odkryli, w jaki sposób glejak wielopostaciowy wymyka się układowi odpornościowemu, indukując makrofagi pro-tumorowe poprzez modyfikację epigenetyczną opartą na glukozie. Zespół odkrył, że kluczem do immunosupresyjnego działania makrofagów, napędzanego metabolizmem glukozy, jest proces zwany laktylacją histonów. W modelach przedklinicznych glejaka wielopostaciowego celowanie w PERK (kinazę eukariotycznego czynnika inicjacji translacji 2α) zaburzało laktylację histonów i immunosupresyjną aktywność makrofagów, a w połączeniu z immunoterapią blokowało progresję glejaka wielopostaciowego i indukowało długotrwałą odporność, która chroniła mózg przed ponownym wzrostem guza1.
Bariera krew-mózg i obrzęk peritumorowy
Mikrośrodowisko i neurotransmisja między tkanką okołoguzową a normalną tkanką mózgową znacznie się różnią. Glejaki powodują przerwanie bariery krew-mózg w otaczającej tkance poprzez zmianę przepuszczalności śródbłonka, co może prowadzić do obrzęku naczyniopochodnego, zmian zapalnych, słabej perfuzji i zmian w hemostazy. Wszystkie te zmiany w mikrośrodowisku w tkance okołoguzowej mogą prowadzić do zaburzenia równowagi sodu i wapnia w komórkach nerwowych, ostatecznie powodując nadpobudliwość i drgawki2.
Obrzęk mózgu związany z guzem mózgu powstaje, ponieważ naczynia włosowate guza nie posiadają normalnej funkcji bariery krew-mózg; czynnik przepuszczalności naczyniowej (VPF, znany również jako naczyniowo-śródbłonkowy czynnik wzrostu, VEGF) jest prawdopodobnym mediatorem tego zjawiska. Deksametazon może zmniejszać przepuszczalność naczyniową związaną z guzem mózgu poprzez dwa mechanizmy zależne od receptora glikokortykoidowego (GR): zmniejszenie odpowiedzi naczyń na pochodzące z guza czynniki przepuszczalności (w tym VPF) oraz zmniejszenie ekspresji VPF przez komórki guza1.
Mechanizmy oporności na leczenie w guzach mózgu
Mimo znaczących postępów w zrozumieniu guzów mózgu oraz poprawy diagnostyki, leczenia i jakości życia pacjentów, wskaźnik śmiertelności z powodu raka mózgu pozostał stabilny przez ponad trzy dekady1. Nowe i rozwijające się immunoterapie guzów mózgu mają potencjał do zmniejszenia szkodliwych skutków i poprawy wskaźników przeżywalności pacjentów z rakiem mózgu2.
Rola komórek macierzystych nowotworów
Guzy mózgu glejaka wielopostaciowego należą do najbardziej śmiertelnych form raka, z pięcioletnim wskaźnikiem przeżycia poniżej 10% dla pacjentów w wieku 45 lat i starszych. Nawet gdy wydaje się, że guzy zostały całkowicie usunięte, prawie zawsze wracają1.
Standardowa terapia dla glejaka wielopostaciowego celuje w aktywnie dzielące się komórki. Jednak istnieje mały odsetek uśpionych, przypominających komórki macierzyste komórek, które unikają tych terapii i inicjują ponowny rozwój guza2. Tradycyjna chemioterapia i radioterapia atakują komórki, które szybko rosną i dzielą się – cecha charakterystyczna większości komórek nowotworowych. Ale w guzach glejaka wielopostaciowego niektóre komórki są w stanie spoczynku. Oznacza to, że są w zasadzie w stanie uśpienia, ukrywając się przed leczeniem skierowanym na podział komórek3.
Badania wykazały, że komórki w stanie spoczynku stopniowo dają początek dzielącym się komórkom, co pozwala guzom ponownie rosnąć1. Te badania wyjaśniają, dlaczego terapie koncentrujące się tylko na podziale komórek są niewystarczające do leczenia glejaka wielopostaciowego i wzmacniają potrzebę opracowania nowych strategii, które celują w komórki w stanie spoczynku2.
Mechanizmy oporności metabolicznej
Badacze zidentyfikowali mechanizm, który wyjaśnia, dlaczego pacjenci z glejakiem wielopostaciowym nie mieli pomyślnych wyników, gdy byli leczeni inhibitorami mTOR, mimo że jest on nadekspresjonowany w około 90% przypadków1.
Badania dotyczące tych procesów doprowadziły naukowców do zbadania relacji między mTOR a genem białaczki promielocytowej (PML). PML jest w stanie hamować mTOR, gdy poziomy mTOR są zbyt wysokie, sprawiając, że komórki są w stanie spoczynku. Chociaż komórki guza rosną wolniej, pozwala to guzowi uniknąć leczenia, czyniąc go mniej zależnym od sygnału, który faktycznie próbujemy celować2.
Badacze odkryli, że gdy pacjent otrzymuje inhibitor mTOR, poziomy białka PML znacznie wzrastają. Odwrócenie tej regulacji w górę PML powoduje, że komórki guza stają się podatne na śmierć komórkową zapośredniczoną przez inhibitor mTOR, co jest oczywiście pożądanym efektem1.
Rola kanałów jonowych w oporności guzów mózgu
Kanały jonowe odgrywają kluczową rolę w guzach mózgu i niepowodzeniu leczenia raka. Celowanie w mechanizmy molekularne i kanały jonowe w przerzutach do mózgu prowadzi do zwiększenia lepszej odpowiedzi u tych pacjentów1.
Pierwszy etap przerzutów, znany jako EMT (epithelial-mesenchymal transition), jest regulowany przez błonę komórkową i wewnątrzkomórkowe kanały jonowe w komórkach nowotworowych, które mają wysoką skłonność do przerzutów do mózgu, takich jak rak płuc i piersi. Badania wskazują, że kanały K+ i Cl- odgrywają rolę w glejakach i pierwotnych nowotworach mózgu2.
Kanały jonowe są kluczowymi modulatorami patofizjologii komórek nowotworowych i odgrywają krytyczne role w progresji raka, takie jak inwazja, migracja, angiogeneza i proliferacja komórek. Celowanie w nie bezpośrednio nie tylko zwiększa skuteczność leczenia, ale także minimalizuje niekorzystne wyniki1.
Badania wykazały, że przepływy jonów chlorkowych, które wchodzą do komórek, odgrywają ważną rolę w replikacji komórek glejaka wielopostaciowego, wysoce agresywnego guza mózgu. Wykorzystując substancje, które blokują te przepływy, grupa badawcza wykazała, że można zatrzymać replikację w komórkach guza hodowanych w laboratorium1.
W szczególności, umożliwiając napływ jonów chlorkowych do komórki, kanały jonowe wydają się pomagać zwiększać objętość komórki, fundamentalny proces, który promuje podział na dwie komórki potomne. Te dowody wskazują, że kanały te odgrywają znaczącą rolę w sprawianiu, że komórka guza rośnie, aby mogła się dzielić i mnożyć, tym samym promując progresję guza. Te same kanały mogą zatem być uznane za potencjalne cele dla nowych leków specjalnie zaprojektowanych do zatrzymania progresji guza1.
Rola autofagii w progresji guza mózgu
Autofagia odgrywa kluczową rolę w rozwoju chorób, szczególnie nowotworów u ludzi, z działaniami, które mogą albo promować przeżycie, albo indukować śmierć komórki1. Guzy mózgu przyczyniają się do wysokiego poziomu zarówno śmiertelności, jak i zachorowalności na całym świecie, przy czym oporność na leczenie jest nabywana z powodu mutacji genetycznych i dysregulacji mechanizmów molekularnych, wśród innych czynników2.
Autofagia może kontrolować rozwój różnych typów guzów mózgu, takich jak glejak wielopostaciowy, glejak i wyściółczak, wykazując jej potencjał w leczeniu. Mechanizmy autofagii mogą wpływać na przerzuty i oporność na leki w glejakach wielopostaciowych, a istnieje złożona interakcja między autofagią a odpowiedziami komórkowymi na stres, takie jak hipoksja i głód3.
Autofagia odgrywa elastyczną rolę w rozwoju GBM, wpływając zarówno na proliferację, jak i przerzuty. Stąd autofagia ma zdolność do kontrolowania rozwoju GBM1. Autofagia jest niezbędna do przeżycia komórek guza w hipoksyjnym obszarze glejaka i przyczynia się do jego agresywności2.
Autofagia odgrywa kluczową rolę w leczeniu raka, blokując początek guza i niszcząc komórki nowotworowe w miarę ich rozwoju. Autofagia odgrywa rolę w regulowaniu starzenia się komórek i zapobieganiu rozwojowi raka1. Uważa się, że autofagia jest głównym czynnikiem w cytotoksycznych skutkach temozolomidu (TMZ), a jej hamowanie znacząco wpływa na przeciwnowotworowe działanie TMZ in vitro2.
Podsumowanie czynników ryzyka i implikacji klinicznych
Przyczyna większości guzów mózgu jest nieznana, chociaż do 4% nowotworów mózgu może być spowodowanych promieniowaniem ze skanów CT. Rzadkie czynniki ryzyka obejmują narażenie na chlorek winylu, wirusa Epsteina-Barra, promieniowanie jonizujące oraz zespoły dziedziczne, takie jak neurofibromatoza, stwardnienie guzowate i choroba von Hippel-Lindaua1.
Mutacje i delecje genów supresorowych guza, takich jak P53, uważa się za przyczynę niektórych form guzów mózgu. Dziedziczne schorzenia, takie jak choroba von Hippel-Lindaua, stwardnienie guzowate, zespół mnogiej gruczolakowatości wewnątrzwydzielniczej i neurofibromatoza typu 2, niosą wysokie ryzyko rozwoju guzów mózgu2.
Ryzyko rozwoju drgawek różni się w zależności od typu guza mózgu, przy czym główne czynniki ryzyka obejmują lokalizację guza, rozmiar, histopatologię i poziom resekcji1.
Klasyfikacja lub stopniowanie guza mózgu umożliwia klinicyście określenie najlepszego sposobu postępowania w leczeniu guza pacjenta po diagnozie. Światowa Organizacja Zdrowia (WHO) wydaje aktualizacje globalnych wytycznych dotyczących klasyfikacji guzów mózgu co kilka lat1.
Rokowniczo wpływ na samopoczucie i zagrożenie życia zależy od rodzaju guza, lokalizacji w mózgu, rozmiaru w momencie diagnozy, tempa wzrostu oraz tego, ile można chirurgicznie usunąć lub skutecznie leczyć1.
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Materiały źródłowe
- #1 Brain tumor – Wikipediahttps://en.wikipedia.org/wiki/Brain_tumor
A brain tumor (sometimes referred more commonly as brain cancer) occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cancerous) tumors. […] The cause of most brain tumors is unknown, though up to 4% of brain cancers may be caused by CT scan radiation. Uncommon risk factors include exposure to vinyl chloride, EpsteinBarr virus, ionizing radiation, and inherited syndromes such as neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau Disease. […] Mutations and deletions of tumor suppressor genes, such as P53, are thought to be the cause of some forms of brain tumor. Inherited conditions, such as Von HippelLindau disease, tuberous sclerosis, multiple endocrine neoplasia, and neurofibromatosis type 2 carry a high risk for the development of brain tumors.
- #1 Brain Tumors – AANShttps://www.aans.org/patients/conditions-treatments/brain-tumors/
Brain tumors are thought to arise when certain genes on the chromosomes of a cell are damaged and no longer function properly. These genes normally regulate the rate at which the cell divides (if it divides at all) and repair genes that fix defects of other genes, as well as genes that should cause the cell to self-destruct if the damage is beyond repair. […] Once a cell is dividing rapidly and internal mechanisms to check its growth are damaged, the cell can eventually grow into a tumor. […] Tumors can produce substances called angiogenesis factors that promote the growth of blood vessels. The new vessels that grow increase the supply of nutrients to the tumor, and, eventually, the tumor becomes dependent on these new vessels.
- #1 Brain Tumor: Symptoms, Signs & Causeshttps://my.clevelandclinic.org/health/diseases/6149-brain-cancer-brain-tumor
Brain tumors can be malignant (cancerous) or benign (noncancerous) and can affect children and adults. […] Brain tumors can impact brain function and your health if they grow large enough to press on surrounding nerves, blood vessels and tissue. […] Researchers know brain tumors develop when certain genes on the chromosomes of a cell are damaged and no longer function properly, but they aren’t sure why this happens. […] When brain cell DNA changes, it gives your brain cells new instructions. Your body develops abnormal brain cells that grow and multiply faster than normal and sometimes live longer than normal. […] In some cases, a person may be born with changes in one or more of these genes. Environmental factors, such as exposure to large amounts of radiation from X-rays or previous cancer treatment, may then lead to further damage.
- #1 Neuronal Brain Tumors – StatPearls – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK576406/
Neuronal brain tumors are a diverse group of primary central nervous system tumors consisting of lesions with either a primarily neuronal background or a mixed glial and neuronal background, termed glioneuronal tumors. […] These tumors may be purely neuronal in origin or have mixed neuronal and glial components, which comprise a subset of glioneuronal tumors. […] The current emphasis on molecular characterization of brain tumors provides new insight into the genetic aberrations that underlie their tumorigenesis. […] Specifically, 2 main molecular subgroups may involve mutations within different cellular regulation pathways. […] The first subgroup demonstrates mutation in the mitogen-activated protein kinase (MAPK) pathway, which is involved in cellular growth. […] The second group demonstrates mutation in fibroblast growth factor (FGFR) genes, mostly FGFR-1, upstream from the MAPK pathway.
- #1 Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma | Nature Reviews Cancerhttps://www.nature.com/articles/nrc2818
Malignant gliomas and medulloblastomas the most common brain tumours affecting adults and children, respectively remain responsible for a disproportionate level of morbidity and mortality among cancer patients. […] Recent integrated genomics has further implicated specific molecular networks in the pathogenesis of gliomas and medulloblastomas. These most prominently include receptor tyrosine kinase (RTK) signalling through the RasMAPK and PI3KAKTmTOR pathways, Wnt signalling and sonic hedgehog (SHH) signalling, along with the cell cycle-regulating RB and p53 pathways. […] This study reports large-scale, integrated genomic analysis revealing the central importance of certain core signalling pathways in the pathogenesis of malignant glioma. […] This study uses an integrated genomics analysis of TCGA data coupled with proteomics in a second large tumour set to link glioma transcriptional subclasses with defined core signalling abnormalities.
- #1 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. […] A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-B, and TGF-, critical to tumor growth, invasion, and treatment resistance. […] In GBM, changes and/or increased activity in crucial signaling pathways such as Wnt, TGF-, VEGF, EGFR, CDKN2A, NF-B, and the PI3K/AKT/mTOR pathway are believed to play a role in the disease’s pathogenesis and contribute to the tumor’s aggressive behavior. […] It is crucial to recognize that human malignant gliomas, including glioblastomas, typically do not rely on a single oncogene or tumor suppressor gene for their initiation and progression.
- #1 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The persistent and aberrant activation of the NF-B signaling pathway is a hallmark of GBM. […] The Wnt signaling pathway is an ancient and fundamental genetic program that provides crucial regulatory instructions for cell growth, differentiation, and tissue patterning. […] The TGF- signaling pathway plays a crucial role in regulating key cellular processes, including proliferation, immune response, apoptosis, and adhesion. […] The MAPK signaling pathway plays a pivotal role in various cancers, including GBM, through its hyperactivation, which drives processes such as migration, proliferation, and survival. […] The p53 gene encodes a protein crucial for regulating cellular stress responses by controlling the expression of target genes involved in vital processes, including cell cycle regulation, apoptosis, differentiation, senescence, DNA repair, and neovascularization.
- #1 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The occurrence of a p53 mutation, often following IDH1/2 mutations, marks a key genetic event, except in Li-Fraumeni syndrome cases. […] The RB (Retinoblastoma Protein) pathway plays a critical role in halting cell cycle initiation and progression, functioning in tandem with the p53 pathway. […] The high prevalence of p53 mutations in GBM underscores their potential as key targets for precision medicine therapies. […] The progression of GBM is driven by a complex network of signaling pathways. […] The SHH signaling pathway is closely linked to the function of the primary cilium (PC), and disrupting PC function may inhibit GBM proliferation, slow malignant progression, and improve treatment sensitivity. […] The mechanisms underlying GBM cell migration and invasion are highly complex, involving interrelated biological processes. […] These findings highlight widespread upregulation of glycolysis and PPP-related genes, which supports elevated ATP and nucleotide production.
- #1 Molecular Pathogenesis of Glioblastoma in Adults and Future Perspectives: A Systematic Reviewhttps://www.mdpi.com/1422-0067/23/5/2607
Loss of cell cycle control is involved in gliomagenesis. […] The G1 checkpoint has been an important topic of research in GBMs, and it mainly involves cyclins and cyclin-dependent kinases (CDK). […] Not surprisingly, 87% of GBM patients have an associated p53 mutation. […] In non-neoplastic cells, DNA repair aims to prevent genetic instability that could lead to tumorigenesis. […] Cancer cells adapt DNA repair mechanisms to play a crucial factor in development of therapy resistance and tumour relapse. […] Glioblastoma cells show over-expression of certain growth factors and their receptors. […] This creates an autocrine growth-promoting loop which provides growth advantage to rapidly proliferating tumour cells. […] The potential role of PI3K in this process has already been discussed above.
- #1 Seizures in brain tumors: pathogenesis, risk factors and management (Review)https://www.spandidos-publications.com/10.3892/ijmm.2025.5523
In neuroinflammation, the microglia and astrocytes secrete pro-inflammatory cytokines (PICs) such as interleukin 1 beta (IL-1), tumor necrosis factor alpha (TNF-) and interleukin 6 (IL-6), among others. […] The overload of PICs in the CNS leads to the blood-brain barrier (BBB) breakdown, resulting in further recruitment of PICs from the systemic circulation. […] This review focuses on the role of IL-1, TNF-, toll-like receptor 4 (TLR4) and High-mobility group box 1 (HMGB1) in BTRE pathophysiology. […] IDH, comprising 3 isoforms, IDH1, IDH2 and IDH3, plays a crucial role in the Krebs cycle, by facilitating the conversion of isocitrate to -ketoglutarate (-KG). […] Missense mutations in the IDH1 gene in gliomas results in the production of 2-hydroxyglutarate (2-HG). […] The proposed mechanism is that 2-HG elevates levels of ribosomal protein S6, which plays a role in mTOR signaling.
- #1 Seizures in brain tumors: pathogenesis, risk factors and management (Review)https://www.spandidos-publications.com/10.3892/ijmm.2025.5523
Tumor suppressor genes phosphatase and tensin homolog (PTEN), tumor protein p53 (TP53) and Neurofibromin 1 (NF1) are affected by these mutations. […] It has been suggested that these changes promote tumorigenesis and subsequent tumor progression, while also contributing to epileptogenesis. […] The aggressive and anarchic growth pattern of glioblastomas (GBM) results in genetic mutations that can be detected even intratumorally. […] The incidence of seizures varies significantly among different types of brain tumors, ranging from 10% to over 80%, contingent upon the tumor type. […] Preoperative risk factors for seizures in brain tumors include sex, tumor location and size, and the presence of peritumoral edema. […] The extent of resection significantly influences the incidence of postoperative seizures across all tumor types.
- #1 Brain tumor – Symptoms and causes – Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/brain-tumor/symptoms-causes/syc-20350084
When brain tumors happen in children, they’re likely to be primary brain tumors. In adults, brain tumors are more likely to be cancer that started somewhere else and spread to the brain. […] Secondary brain tumors happen when cancer starts somewhere else and spreads to the brain. When cancer spreads, it’s called metastatic cancer. […] In adults, secondary brain tumors are far more common than are primary brain tumors.
- #1 Neuro-Oncology | OncologyPROhttps://oncologypro.esmo.org/education-library/esmo-books/essentials-for-clinicians/neuro-oncology/1-epidemiology-pathogenesis-risk-factors-of-brain-tumours
Brain tumours is the common term to define central nervous system (CNS) neoplasms, or CNS tumours. […] The 2016 World Health Organization classification of CNS tumours is based on histopathological and molecular criteria and includes malignant, benign and borderline tumours. They are categorised as primary or secondary. […] Primary CNS tumours include all primary tumours located in the CNS, the envelopes of the CNS and the beginning of the nerves localised in the skull and spine. […] Secondary CNS tumours are CNS metastases; they are all malignant. CNS metastases are single or multiple. […] Metastatic tumours are the most frequent type of CNS tumour in adults. The reported incidence of metastatic CNS tumours is increasing but the exact incidence is unknown. […] In general, the sources of brain metastases (in descending order) are: cancers of the lung, breast, skin (melanoma), kidney and gastrointestinal tract.
- #1 Brain Neoplasms: Practice Essentials, Pathophysiology, Etiologyhttps://emedicine.medscape.com/article/779664-overview
Tumors of the brain produce neurologic manifestations through a number of mechanisms. Small, critically located tumors may damage specific neural pathways traversing the brain. Tumors can invade, infiltrate, or supplant normal parenchymal tissue, disrupting normal function. Because the brain dwells in the limited volume of the cranial vault, growth of intracranial tumors with accompanying edema may cause increased intracranial pressure. Tumors adjacent to the third and fourth ventricles may impede the flow of cerebrospinal fluid, leading to obstructive hydrocephalus. In addition, tumors generate new blood vessels (ie, angiogenesis), disrupting the normal blood-brain barrier and promoting edema. […] The cumulative effects of tumor invasion, edema, and hydrocephalus may elevate the intracranial pressure (ICP) and impair cerebral perfusion. Intracranial compartmental rise in ICP may provoke shifting or herniation of tissue under the falx cerebri, through the tentorium cerebelli, or through the foramen magnum.
- #1 Signaling pathways in brain tumors and therapeutic interventions | Signal Transduction and Targeted Therapyhttps://www.nature.com/articles/s41392-022-01260-z
The vascular endothelial growth factor receptor (VEGFR) signaling pathway has been considered a key factor in GBM tumor survival. […] The transforming growth factor beta (TGF-) protein family has complicated functions in diverse regulatory pathways, where TGF-2 is a T cell inhibitor in the GBM tumor microenvironment that is found in approximately 90% of GBM tumor cells. […] Wingless and int-1 (Wnt) signaling modulates the neural progenitor cell (NPC) self-renewal, proliferation, as well as differentiation in the brain at varying stages of CNS development. […] The above crucial signaling pathways involved in glioma were demonstrated in Fig. 2.
- #1 Overview of Intracranial Tumors – Neurologic Disorders – Merck Manual Professional Editionhttps://www.merckmanuals.com/professional/neurologic-disorders/intracranial-and-spinal-tumors/overview-of-intracranial-tumors
Neurologic dysfunction may result from the following: […] A malignant tumor can develop new internal blood vessels, which can bleed or become occluded, resulting in necrosis and neurologic dysfunction that mimics stroke. […] Benign tumors grow slowly. They may become quite large before causing symptoms, partly because often there is no cerebral edema. Malignant primary tumors grow rapidly but rarely spread beyond the CNS. Death results from local tumor growth and/or tumor-related hemorrhage and thus can result from benign as well as malignant tumors.
- #1 Brain Tumor: A Comprehensive Guide by Dr. Kamran Aghayevhttps://kamranaghayev.com/brain-tumor/
A brain tumor is an abnormal growth in the brain, causing compression and loss of important functions. […] A growing tumor has to come at the expense of losing the volume of other components in the cranial cavity. Therefore, the brain tissue, cerebrospinal fluid and blood in the brain circulation have to retract to make extra room for space occupying tumor. This mechanism is called compensation and at this stage the intracranial pressure is not elevated. […] Once compensation mechanisms have been exhausted the intracranial pressure rapidly rises leading to life threatening disruptions of vital brain functions. […] Pain is caused either by elevated intracranial pressure compressing and stretching the dura mater or due to direct invasion of the dura by tumor. […] Gliomas originate and grow inside of the brain.
- #1 Brain Neoplasms: Practice Essentials, Pathophysiology, Etiologyhttps://emedicine.medscape.com/article/779664-overview
Most primary brain tumors do not metastasize, but if they do metastasize, intracranial spread generally precedes distant dissemination. […] Metastatic brain tumors from non-CNS primary tumors may be the first sign of malignancy, or they may herald a relapse. Nonetheless, the signs and symptoms of brain metastases simulate those of primary brain tumors. […] Leptomeningeal infiltration may present with dysfunction of multiple cranial nerves.
- #1 Brain Tumor: Symptoms, Signs & Causeshttps://my.clevelandclinic.org/health/diseases/6149-brain-cancer-brain-tumor
Approximately 78% of cancerous primary brain tumors are gliomas. These tumors develop in glial cells, which surround and assist nerve cells. […] Medulloblastoma is another type of cancerous brain tumor. These tumors are fast growing and form at the base of your skull. They’re the most common cancerous brain tumor in children. […] Brain tumors whether cancerous or not can cause serious problems. […] Brain tumors can cause problems by directly invading and destroying healthy brain tissue, putting pressure on nearby tissue, increasing pressure within your skull (intracranial pressure), causing fluid to build up in your brain, blocking the normal flow of cerebrospinal fluid (CSF) through the spaces within your brain, causing those spaces to enlarge, and causing bleeding in your brain.
- #1 The Radiology Assistant : Systematic Approach to Brain Tumorshttps://radiologyassistant.nl/neuroradiology/brain-tumor/systematic-approach
Astrocytomas spread along the white matter tracts and do not respect the boundaries of the lobes. […] Because of this infiltrative growth, in many cases the tumor is actually larger than can be depicted with MR. […] Some tumors show subarachnoid seeding and form tumoral nodules along the brain and spinal cord. […] The ability of tumors to cross the midline limits the differential diagnosis. […] Glioblastoma multiforme (GBM) frequently crosses the midline by infiltrating the white matter tracts of the corpus callosum. […] Multiple tumors in the brain usually indicate metastatic disease. […] Primary brain tumors are typically seen in a single region, but some brain tumors like lymphomas, multicentric glioblastomas and gliomatosis cerebri can be multifocal. […] Most intra-axial tumors are located in the white matter.
- #1 Signaling pathways in brain tumors and therapeutic interventions | Signal Transduction and Targeted Therapyhttps://www.nature.com/articles/s41392-022-01260-z
Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. […] Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor. Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies. Thus, there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors, which might result in greater progress in therapeutic approaches. […] The major signaling pathways underlying these brain tumors pathogenesis and current progress in therapies, including clinical trials, targeted therapies, immunotherapies, and system therapies, have been systemically reviewed and discussed.
- #1 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
Epigenetic modifications play a pivotal role in the development of GBM, with approximately 50% of newly diagnosed cases showing methylation of the MGMT promoter. […] Genomic studies of GBM have unveiled several critical signaling pathways and genetic mutations that drive the tumor’s progression. […] The presence of multiple dysregulated signaling pathways in GBM underscores the idea that tumors rely on the disruption of various molecular targets, which collectively influence tumor biology. […] The PI3K/AKT/mTOR intracellular signaling pathway plays a crucial role in regulating various cellular processes, including growth, proliferation, and metabolism. […] Dysregulation of PI3K/AKT/mTOR signaling is commonly observed in many cancers, contributing to tumorigenesis by promoting uncontrolled cell growth, survival, and resistance to apoptosis.
- #1 Current understanding of gliomagenesis: from model to mechanismhttps://www.medsci.org/v19p2071.htm
Several methods of genetic modification, including RCAS/t-va, Cre-loxP, zinc finger nucleases (ZFNs), and Tal-effector nuclease (TALENs), have introduced a new dimension in the development of genome manipulation at the molecular level. […] Therefore, it is essential to highlight the benefits of developing a new glioma model using CRISPR/Cas9 to better understand the molecular mechanisms of gliomagenesis and establish better therapeutic methods. […] In gliomas, another commonly identified pathway is TP53 signaling pathway. As the most common tumor suppressor gene, TP53 mutation is critical for the progression of glioma. […] The RTK/RAS/PI3K pathways promote cell survival. PI3Ks, a family of heterodimeric kinases, have been reported to contain genetic alterations in 88% of GBM cases. […] Therefore, the inhibition of the components of RB1 pathway might be a promising strategy for the treatment of various malignant cancer types, including astrocytoma, adenocarcinoma, basal cell carcinoma, and gastrointestinal tract endocrine tumor.
- #1 Molecular pathogenesis of glioblastoma multiforme: Nuances, obstacles, and implications for treatmenthttps://www.wjgnet.com/2218-6212/full/v5/i3/88.htm
One important concept that helps to explain this in part is chemotherapy resistance and in the case of temozolomide, through damaged DNA repair. […] The AGT protein removes the alkylated moiety on the O6 position of guanine and renders the therapeutic modality of temozolomide obsolete. […] The LOH phenomenon specifically involving alleles of tumor suppressor genes in parts or all of chromosome 10q has reliably been demonstrated in the molecular pathogenesis of GBM. […] The wild type PTEN gene is a tumor suppressor. […] When PTEN activity is lost through mutation or LOH, PIP3 accumulates and begets malignant growth though constitutive activation of the PI3K/Akt pathway. […] The next molecular phenomenon in GBM pathogenesis to be discussed is the 1p/19q codeletion. […] IDH-wild-type gliomas include grade I pilocytic astrocytomas and primary GBMs.
- #1 The molecular mechanism behind elevated TGF-beta levels in the most aggressive brain tumor revealed – VHIOhttps://vhio.net/2014/09/08/the-molecular-mechanism-behind-elevated-tgf-beta-levels-in-the-most-aggressive-brain-tumor-revealed-2/
Latest research from the Vall dHebron Institute of Oncology (VHIO) in Barcelona, recently published in the prestigious journal Cancer Discovery, has revealed the molecular mechanisms that lead to high levels of TGF-beta in some glioma patients. […] In patients with high levels of TGF-beta, however, neither mechanism has been observed, comments Joan Seoane as he explains what stimulated this particular line of research. […] A looping effect is therefore triggered whereby high levels of TGF-beta promote an even greater production of TGF-beta. […] TGF-beta induces an increase in RNA for TGF-beta transcription. This means that it continues to send signals to further increase activity at the production line. […] For the very first time, this study has identified what is responsible for issuing the production chain its orders: CREB, the Director of Operations in this process.
- #1 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugshttps://www.explorationpub.com/Journals/en/Article/100640
Brain metastasis is the most prevalent neurologic problem of systemic cancer and it can increase the mortality rate in patients with cancer. […] Significant interactions between cancer cells, the brain microenvironment, and the blood-brain barrier (BBB) play a major role in brain metastasis. […] There are significant impacts of ion channels in brain metastasis and cancer treatment failure. Targeting molecular mechanisms and ion channels in brain metastasis led to increasing the better response in these patients. […] The first stage of metastasis, known as EMT, is regulated by the plasma membrane and intracellular ion channels in cancer cells that have a high propensity for brain metastasis, such as lung and breast cancer. […] Research indicates that K+ and Cl channels play a role in gliomas and primary brain cancers.
- #1 Pathogenesis and Management of Brain Tumor-Related Epilepsy – Gliomas – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK570699/
Up to 50% of patients with brain tumors will initially present with seizures, while an additional 10-30% will develop seizures during the course of the disease. Gliomas are the most common primary intracranial tumors and are associated with a number of changes which are involved in the pathogenesis of epilepsy, including blood-brain barrier disruption, molecular changes, edema, and peritumoral environmental changes. […] The exact pathophysiology of BTRE is not well characterized; however, it is thought to be multifactorial. Tumor burden, type, location, growth rate, microenvironment of the blood-brain barrier, altered neurotransmitter homeostasis, and gap junction alterations are factors that influence BTRE. […] The pathogenesis of epilepsy differs among the various types of tumors. Tumors such as DNETs have high incidence of seizure because they tend to cause cortical disruption due to disruption of the underlying cortical and subcortical structures. The mechanisms behind the higher seizure frequency of other low-grade lesions is likely secondary to mechanical and vascular changes which slowly develop overtime. In contrast, high-grade gliomas and other rapidly dividing tumors tend to cause seizures because of irritation from necrosis or products of hemorrhage, such as hemosiderin.
- #1 Pathogenesis and Management of Brain Tumor-Related Epilepsy – Gliomas – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK570699/
Various animal and human tissue studies have identified glutamate, -aminobutyric acid (GABA), and adenosine kinase (ADK) as possible contributory factors for epileptogenesis in patients with brain tumors. Glioma studies in animals illustrated that seizure activity originated due to elevated glutamate production causing hyperexcitability around the peritumoral area. […] The genetic implications of BTRE are poorly understood. Genes such as LGI1 (a tumor-suppressor gene) and phosphatase and tensin homolog (PTEN) have been associated with gliomas and epilepsy; however, their exact role in epileptogenesis is not well characterized. The microenvironment and neurotransmission between peritumoral tissue and normal brain tissue is vastly different. Gliomas cause disruption of the blood-brain barrier in surrounding tissue by changing the endothelial permeability which can lead to vasogenic edema, inflammatory changes, poor perfusion, and changes in hemostasis. All these microenvironmental changes in peritumoral tissue can lead to sodium and calcium imbalance in the neuronal cells eventually causing hyperexcitability and seizures.
- #1 Mechanism in brain cancer responsible for neuron death discovered | ScienceDailyhttps://www.sciencedaily.com/releases/2011/11/111103120349.htm
Researchers have discovered a mechanism by which glioblastoma multiforme (GBM), the most common form of brain cancer, promotes the loss of function or death of neurons, a process known as neurodegeneration. […] The research revealed that the oncogene (a gene with the ability to cause cancer) astrocyte elevated gene (AEG)-1 promotes neurodegeneration by increasing glutamate toxicity to neurons. […] This study is the first of its kind in that it provides a direct mechanistic link between GBM, neurodegeneration and glutamate transport and explains a process by which GBM, through expression of the AEG-1 oncogene, can provoke the death of neurons. […] AEG-1 inhibits expression of EEAT2 during transcription, the process by which genes are expressed in the nucleus of cells, through several mechanisms that lead to excitotoxicity due to excessive glutamate. […] Understanding glutamate transport is very important for a variety of neurodegenerative diseases, including glioma-induced neurodegeneration.
- #1 Seizures in brain tumors: pathogenesis, risk factors and management (Review)https://www.spandidos-publications.com/10.3892/ijmm.2025.5523
Seizures in the context of brain tumors are a relatively common symptom, with higher occurrence rates observed in glioneuronal tumors and gliomas. […] Brain tumor-related epilepsy (BTRE) is a challenging entity because the pathophysiological mechanisms are not fully understood yet. Nonetheless, neuroinflammation is considered to play a pivotal role. […] Findings on the pathogenesis of BTRE have established that certain genetic mutations are involved, of which the most known would be IDH mutations in gliomas. […] In general, various mechanisms, including mechanical (compression), vascular (imbalance in vascularization), chemical (neurotransmitter dysregulation), and inflammatory processes, have been identified in the pathophysiology of BTRE. […] Inflammation has always played a role in epilepsy, as evidenced by the existence of febrile seizures. This indicates a mechanism through which inflammation induces a hyper-excitable state in brain tissue.
- #1 Wistar Scientists Discover New Immunosuppressive Mechanism in Brain Cancer – The Wistar Institutehttps://www.wistar.org/press-releases/wistar-scientists-discover-new-immunosuppressive-mechanism-in-brain-cancer/
By programming certain immune cells like macrophages, (such as monocyte-derived macrophages and microglia), to work for rather than against the tumor, glioblastoma fosters a tumor microenvironment for itself that enables the cancer to grow aggressively while evading anticancer immune responses. […] The team discovered the key to macrophages glucose-metabolism-driven immunosuppressive potency lies in a process called histone lactylation. […] The team demonstrated that glioblastoma-perturbed glucose metabolism in these macrophages induced their immunosuppressive activity. […] In preclinical models of glioblastoma, targeting PERK impaired histone lactylation and immunosuppressive activity of macrophages, and in combination with immunotherapy blocked glioblastoma progression and induced long-lasting immunity that protected the brain from tumor re-growth a sign that targeting PERK-histone lactylation axis may be a viable strategy for fighting this deadly brain cancer.
- #1https://www.jci.org/articles/view/118927
Brain tumor-associated cerebral edema arises because tumor capillaries lack normal blood-brain barrier function; vascular permeability factor (VPF, also known as vascular endothelial growth factor, VEGF) is a likely mediator of this phenomenon. […] Our goals were to determine if suppression of permeability by dexamethasone might involve inhibition of VPF action or expression, and if dexamethasone effects in this setting are mediated by the glucocorticoid receptor (GR). […] Dexamethasone may decrease brain tumor-associated vascular permeability by two GR-dependent mechanisms: reduction of the response of the vasculature to tumor-derived permeability factors (including VPF), and reduction of VPF expression by tumor cells.
- #1 Immunotherapy for Brain Cancer – Cancer Research Institutehttps://www.cancerresearch.org/cancer-types/brain-cancer
Cancers of the brain and nervous system affect both adults and children, and come in several different forms. The cause of these cancers is not yet well understood. […] Glioblastoma (GBM), which forms from astrocytes, is the most dangerous and aggressive form of brain cancer. […] Despite significant advances in the understanding of brain cancer, and improvements to diagnosis, treatments, and patient quality of life, the mortality rate for brain cancer has remained consistent for more than three decades. […] New and developing brain cancer immunotherapies have the potential to reduce the harmful effects and improve survival rates for patients with brain cancer.
- #1 Why Do Brain Tumors Often Return After Treatment? MSK Researchers Say Stem Cells May Be Key | Memorial Sloan Kettering Cancer Centerhttps://www.mskcc.org/news/why-do-brain-tumors-often-return-after-treatment-msk-researchers-say-stem-cells-may-be-key
Glioblastoma brain tumors are one of the most deadly forms of cancer, with a five-year survival rate of less than 10% for patients 45 and older. Even when the tumors look as if they have been fully removed, they almost always come back. […] The standard therapy for glioblastoma targets actively dividing cells, says BTC Director Luis Parada, the papers senior author, who came to MSK in 2015 to develop a comprehensive program for fighting brain tumors. But here, we demonstrate the existence of a small percentage of dormant, stem-like cells that evade these therapies and reinitiate tumor development. […] Traditional chemotherapy and radiation therapy go after cells that are quickly growing and dividing a characteristic of most cancer cells. But in glioblastoma tumors, some cells are quiescent. That means they are essentially in a dormant, resting state hiding out from treatments aimed at cell division.
- #1 Why Do Brain Tumors Often Return After Treatment? MSK Researchers Say Stem Cells May Be Key | Memorial Sloan Kettering Cancer Centerhttps://www.mskcc.org/news/why-do-brain-tumors-often-return-after-treatment-msk-researchers-say-stem-cells-may-be-key
We found that quiescent cells very gradually give rise to dividing cells, which allow tumors to grow again, explains Dr. Parada, who is a member of the Cancer Biology and Genetics Program in the Sloan Kettering Institute. […] This research shows why therapies that focus only on cell division are insufficient for treating glioblastoma and reinforce the need for developing new strategies that target quiescent cells, Dr. Parada says. The discovery of activated cancer stem cells in mouse models provides us with unprecedented opportunity to investigate their unique features and self-renewal mechanisms, which will help in our ongoing efforts to find a cure for glioblastoma.
- #1 New Mechanism of Resistance Identified in Brain Tumorshttps://www.onclive.com/view/new-mechanism-of-resistance-identified-in-brain-tumors
Researchers have identified a mechanism that explains why patients with glioblastoma have not had successful outcomes when treated with inhibitors of mTOR despite the fact that it is overexpressed in approximately 90% of cases. […] Understanding the mechanisms of acquired resistance is essential for developing more effective treatments for patients that combine mTOR inhibitors with other agents to suppress this resistance, Mischel said. […] Investigations into these processes led Mischel and colleagues to study the relationship between mTOR and the promyelocytic leukemia (PML) gene. […] Mischel said that PML is able to suppress mTOR when mTOR levels are too high, making the cells quiescent in the process. […] Although the tumor cells grow more slowly, it enables the tumor to escape the treatment by rendering the tumor less dependent on the signal that you’re actually trying to target, Mischel said.
- #1 New Mechanism of Resistance Identified in Brain Tumorshttps://www.onclive.com/view/new-mechanism-of-resistance-identified-in-brain-tumors
The researchers found that when a patient receives an mTOR inhibitor, PML protein levels rise markedly. […] Reversing this upregulation of PML causes the tumor cells to be vulnerable to mTOR inhibitor-mediated cell death, which is of course the desired outcome, Mischel said. […] Mischel said that low-dose arsenic could be used in combination with mTOR inhibitors to address PML activity. […] The fact is that there is really sound science behind this, and this is at a level that’s below the poisonous threshold, Mischel said. […] It is likely that there may be differences in response to these agents based upon molecular context, but at this point, the data suggest that the target is activated in the majority of these patients, and that they are likely to be able to safely take these drugs, Mischel said.
- #1 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugshttps://www.explorationpub.com/Journals/en/Article/100640
Ion channels are crucial modulators of the pathophysiology of cancer cells. […] Ion channels have critical roles in cancer progress such as invasion, migration, angiogenesis, and cell proliferation. […] Targeting them directly not only increases the efficiency of treatment but also minimizes unfavorable outcomes. […] The use of nanomedicines and new methods in drug delivery can be a breakthrough in this field. […] Developing a nanodrug to regulate ion channels implicated in brain metastasis has the potential to transform cancer therapy and is an appealing avenue for further investigation.
- #1 Mechanism Helping Brain Cancer Cells Multiply Discovered | Technology Networkshttps://www.technologynetworks.com/cancer-research/news/mechanism-helping-brain-cancer-cells-multiply-discovered-392011
Chloride ion flows that enter the cells play an important role in the duplication of glioblastoma cells, a highly aggressive brain tumor. […] The study revealed that socalled Calcium-dependent chloride ion channels, which act like gates regulating chloride ion flows in and out of the cell, play a role in regulating tumor cell lines division and thus their proliferation. […] By using substances that block these flows, the research group demonstrated that it is possible to stop replication in tumor cells cultured in the laboratory. […] Glioblastoma is the most common and malignant tumor among neoplasms of the non-neuronal cellular component of the central and peripheral nervous system, generally called glia. […] By doing so, the researchers demonstrated that chloride ion channels indeed have a direct influence on the replication of these cells.
- #1 Mechanism Helping Brain Cancer Cells Multiply Discovered | Technology Networkshttps://www.technologynetworks.com/cancer-research/news/mechanism-helping-brain-cancer-cells-multiply-discovered-392011
In particular, by allowing the influx of chloride ions into the cell they seem to help increase the cell’s volume, a fundamental process that promotes division into two daughter cells. […] This evidence, the researchers explain, indicates that these channels play a significant role in making the tumor cell grow so that it can divide and multiply, thereby promoting tumor progression. […] These same channels could therefore be considered potential targets for novel drugs specifically designed to halt tumor progression.
- #1 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. […] Brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. […] The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. […] Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. […] Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation.
- #1 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a flexible role in the development of GBM, impacting both proliferation and metastasis. […] Hence, autophagy has the ability to control advancement of GBM. […] The role of autophagy in governing the advancement of glioma has been examined alongside GBM. […] Autophagy plays a two-fold role in controlling the advancement of glioma. […] Autophagy has also been extensively recorded in controlling the development of different brain tumors including medulloblastoma. […] The modulation of autophagy as a potential factor in the advancement of brain tumors and its manipulation (whether triggered or blocked) could be considered in the therapy for these malignancies. […] Autophagy is vital for the survival of tumor cells in the hypoxic glioma region and contributes to its aggressiveness.
- #1 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a crucial role in treating cancer by blocking the start of tumors and destroying cancer cells as they advance. […] Autophagy plays a role in regulating senescence and preventing cancer development. […] Autophagy is proposed as the primary factor in the cytotoxic effects of TMZ and inhibiting it significantly impacts TMZ’s anti-tumor effects in vitro. […] Autophagy plays a role in regulating drug resistance in brain tumors. […] There is growing evidence indicating that autophagy plays a role in regulating drug resistance in brain tumors. […] The failure to treat brain tumors is due to the ineffectiveness of conventional methods in causing cell death. […] The new therapeutics can be developed based on targeting autophagy for accelerating therapy and improving response to conventional therapeutics, including chemotherapy. […] Both promoting and blocking autophagy are proposed as potential therapies for brain tumors.
- #1 Seizures in brain tumors: pathogenesis, risk factors and management (Review)https://www.spandidos-publications.com/10.3892/ijmm.2025.5523
Overall, further research on this topic is necessary. […] BTRE remains a crucial public health concern, with its pathophysiological mechanisms not yet fully elucidated. Neuroinflammation significantly contributes, as do genetic mutations. […] The risk of seizure development varies with the type of brain tumor, with prevalent risk factors encompassing tumor location, size, histopathology and level of resection.
- #1https://braintumourresearch.org/pages/information-what-are-brain-tumours?srsltid=AfmBOoqmZNNkdnwb7AdKCSnYX-6J_BjmWeQpcFDyopGixYOtLXbR-0sY
A low-grade tumour is normally classified as a grade 1 or grade 2 brain tumour, according to the World Health Organisation (WHO) classification guidelines. […] A high-grade brain tumour usually comes back after treatment, even if it appears to have been completely eradicated the first time. […] Classification or grading of a persons brain tumour enables a clinician to determine the best course of action in treating a patients tumour after diagnosis. […] The World Health Organisation (WHO) issues updates to the global guidelines for the classification of brain tumours every few years.
- #1https://braintumourresearch.org/pages/information-what-are-brain-tumours?srsltid=AfmBOoqmZNNkdnwb7AdKCSnYX-6J_BjmWeQpcFDyopGixYOtLXbR-0sY
A brain tumour occurs as a result of an abnormal growth or spread of cells from within the brain, or its supporting tissues, that can damage the brain or threaten its function. […] No single, definitive cause has yet been identified for primary brain tumours. […] Like all tumours and cancers, mutations in the DNA of a cell leads to abnormal growth (uncontrolled division), but what causes these mutations is likely to vary between individuals. […] The prognosis impact on well-being and threat to life is dependent on the type of tumour, location in the brain, size at time of diagnosis, growth rate and how much can be surgically removed or successfully treated. […] A primary brain tumour is one that has originated in the brain. […] A secondary brain tumour, also known as a metastatic brain tumour, is one that has developed from cancer that began in another part of the body and then spread (metastasised) to the brain.
- #2 Brain tumors: overview of types, diagnosis, treatment options | Cincinnati, OH Mayfield Brain & Spinehttps://mayfieldclinic.com/pe-braintumor.htm
A brain tumor is an abnormal growth of cells inside the brain or skull; some are benign, others malignant. Tumors can grow from the brain tissue itself (primary), or cancer from elsewhere in the body can spread to the brain (metastasis). Normal cells grow in a controlled manner as new cells replace old or damaged ones. For reasons not fully understood, tumor cells reproduce uncontrollably. A primary brain tumor is an abnormal growth that starts in the brain and usually does not spread to other parts of the body. Primary brain tumors may be benign or malignant. A malignant brain tumor grows quickly, has irregular boundaries, and spreads to nearby brain areas. Whether a brain tumor is benign, malignant, or metastatic, all are potentially life-threatening. Enclosed within the bony skull, the brain cannot expand to make room for a growing mass. As a result, the tumor compresses and displaces normal brain tissue. Some brain tumors cause a blockage of cerebrospinal fluid (CSF) that flows around and through the brain. This blockage increases intracranial pressure and can enlarge the ventricles (hydrocephalus). Some brain tumors cause swelling (edema). Size, pressure, and swelling all create „mass effect,” which cause many of the symptoms. Medical science neither knows what causes brain tumors nor how to prevent primary tumors that start in the brain. Tumors can affect the brain by destroying normal tissue, compressing normal tissue, or increasing intracranial pressure. How well a tumor will respond to treatment, remain in remission, or recur after treatment depends on the specific tumor type and location. A recurrent tumor may be a tumor that still persists after treatment, one that grows back some time after treatment destroyed it, or a new tumor that grows in the same place as the original one.
- #2 Brain tumor – Symptoms and causes – Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/brain-tumor/symptoms-causes/syc-20350084
A brain tumor can form in the brain cells, or it can begin elsewhere and spread to the brain. As the tumor grows, it creates pressure on and changes the function of surrounding brain tissue, which causes signs and symptoms such as headaches, nausea and balance problems. […] Brain tumors happen when cells in or near the brain get changes in their DNA. A cell’s DNA holds the instructions that tell the cell what to do. The changes tell the cells to grow quickly and continue living when healthy cells would die as part of their natural life cycle. This makes a lot of extra cells in the brain. The cells can form a growth called a tumor. […] It’s not clear what causes the DNA changes that lead to brain tumors. For many people with brain tumors, the cause is never known. Sometimes parents pass DNA changes to their children. The changes can increase the risk of having a brain tumor. These hereditary brain tumors are rare.
- #2 Glioma – Symptoms and causes – Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/glioma/symptoms-causes/syc-20350251
Gliomas begin in the gluey supportive (glial cells) that surround nerve cells in the brain. […] Glioma is a growth of cells that starts in the brain or spinal cord. […] The DNA changes tell the cells to make more cells quickly. The cells continue living when healthy cells would die. This causes too many cells that don’t work right. The cells form a mass called a tumor. […] Some gliomas develop more changes in their DNA that cause them to become brain cancers. The changes tell the cells to invade and destroy healthy brain tissue.
- #2 Neuronal Brain Tumors – StatPearls – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK576406/
Neuronal brain tumors are a diverse group of primary central nervous system tumors consisting of lesions with either a primarily neuronal background or a mixed glial and neuronal background, termed glioneuronal tumors. […] These tumors may be purely neuronal in origin or have mixed neuronal and glial components, which comprise a subset of glioneuronal tumors. […] The current emphasis on molecular characterization of brain tumors provides new insight into the genetic aberrations that underlie their tumorigenesis. […] Specifically, 2 main molecular subgroups may involve mutations within different cellular regulation pathways. […] The first subgroup demonstrates mutation in the mitogen-activated protein kinase (MAPK) pathway, which is involved in cellular growth. […] The second group demonstrates mutation in fibroblast growth factor (FGFR) genes, mostly FGFR-1, upstream from the MAPK pathway.
- #2 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
Epigenetic modifications play a pivotal role in the development of GBM, with approximately 50% of newly diagnosed cases showing methylation of the MGMT promoter. […] Genomic studies of GBM have unveiled several critical signaling pathways and genetic mutations that drive the tumor’s progression. […] The presence of multiple dysregulated signaling pathways in GBM underscores the idea that tumors rely on the disruption of various molecular targets, which collectively influence tumor biology. […] The PI3K/AKT/mTOR intracellular signaling pathway plays a crucial role in regulating various cellular processes, including growth, proliferation, and metabolism. […] Dysregulation of PI3K/AKT/mTOR signaling is commonly observed in many cancers, contributing to tumorigenesis by promoting uncontrolled cell growth, survival, and resistance to apoptosis.
- #2 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. […] A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-B, and TGF-, critical to tumor growth, invasion, and treatment resistance. […] In GBM, changes and/or increased activity in crucial signaling pathways such as Wnt, TGF-, VEGF, EGFR, CDKN2A, NF-B, and the PI3K/AKT/mTOR pathway are believed to play a role in the disease’s pathogenesis and contribute to the tumor’s aggressive behavior. […] It is crucial to recognize that human malignant gliomas, including glioblastomas, typically do not rely on a single oncogene or tumor suppressor gene for their initiation and progression.
- #2 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The occurrence of a p53 mutation, often following IDH1/2 mutations, marks a key genetic event, except in Li-Fraumeni syndrome cases. […] The RB (Retinoblastoma Protein) pathway plays a critical role in halting cell cycle initiation and progression, functioning in tandem with the p53 pathway. […] The high prevalence of p53 mutations in GBM underscores their potential as key targets for precision medicine therapies. […] The progression of GBM is driven by a complex network of signaling pathways. […] The SHH signaling pathway is closely linked to the function of the primary cilium (PC), and disrupting PC function may inhibit GBM proliferation, slow malignant progression, and improve treatment sensitivity. […] The mechanisms underlying GBM cell migration and invasion are highly complex, involving interrelated biological processes. […] These findings highlight widespread upregulation of glycolysis and PPP-related genes, which supports elevated ATP and nucleotide production.
- #2 Seizures in brain tumors: pathogenesis, risk factors and management (Review)https://www.spandidos-publications.com/10.3892/ijmm.2025.5523?text=fulltext
In neuroinflammation, the microglia and astrocytes secrete pro-inflammatory cytokines (PICs) such as interleukin 1 beta (IL-1), tumor necrosis factor alpha (TNF-), and interleukin 6 (IL-6), among others. […] The overload of PICs in the CNS leads to the blood-brain barrier (BBB) breakdown, resulting in further recruitment of PICs from the systemic circulation. […] This review focuses on the role of IL-1, TNF-, toll-like receptor 4 (TLR4), and High-mobility group box 1 (HMGB1) in BTRE pathophysiology. […] IDH, comprising 3 isoforms, IDH1, IDH2, and IDH3, plays a crucial role in the Krebs cycle, by facilitating the conversion of isocitrate to -ketoglutarate (-KG). […] Missense mutations in the IDH1 gene in gliomas result in the production of 2-hydroxyglutarate (2-HG). […] The proposed mechanism is that 2-HG elevates levels of ribosomal protein S6, which plays a role in mTOR signaling.
- #2 Brain tumor – Symptoms and causes – Mayo Clinichttps://www.mayoclinic.org/diseases-conditions/brain-tumor/symptoms-causes/syc-20350084
When brain tumors happen in children, they’re likely to be primary brain tumors. In adults, brain tumors are more likely to be cancer that started somewhere else and spread to the brain. […] Secondary brain tumors happen when cancer starts somewhere else and spreads to the brain. When cancer spreads, it’s called metastatic cancer. […] In adults, secondary brain tumors are far more common than are primary brain tumors.
- #2 Neuro-Oncology | OncologyPROhttps://oncologypro.esmo.org/education-library/esmo-books/essentials-for-clinicians/neuro-oncology/1-epidemiology-pathogenesis-risk-factors-of-brain-tumours
Brain tumours is the common term to define central nervous system (CNS) neoplasms, or CNS tumours. […] The 2016 World Health Organization classification of CNS tumours is based on histopathological and molecular criteria and includes malignant, benign and borderline tumours. They are categorised as primary or secondary. […] Primary CNS tumours include all primary tumours located in the CNS, the envelopes of the CNS and the beginning of the nerves localised in the skull and spine. […] Secondary CNS tumours are CNS metastases; they are all malignant. CNS metastases are single or multiple. […] Metastatic tumours are the most frequent type of CNS tumour in adults. The reported incidence of metastatic CNS tumours is increasing but the exact incidence is unknown. […] In general, the sources of brain metastases (in descending order) are: cancers of the lung, breast, skin (melanoma), kidney and gastrointestinal tract.
- #2 Brain Neoplasms: Practice Essentials, Pathophysiology, Etiologyhttps://emedicine.medscape.com/article/779664-overview
Tumors of the brain produce neurologic manifestations through a number of mechanisms. Small, critically located tumors may damage specific neural pathways traversing the brain. Tumors can invade, infiltrate, or supplant normal parenchymal tissue, disrupting normal function. Because the brain dwells in the limited volume of the cranial vault, growth of intracranial tumors with accompanying edema may cause increased intracranial pressure. Tumors adjacent to the third and fourth ventricles may impede the flow of cerebrospinal fluid, leading to obstructive hydrocephalus. In addition, tumors generate new blood vessels (ie, angiogenesis), disrupting the normal blood-brain barrier and promoting edema. […] The cumulative effects of tumor invasion, edema, and hydrocephalus may elevate the intracranial pressure (ICP) and impair cerebral perfusion. Intracranial compartmental rise in ICP may provoke shifting or herniation of tissue under the falx cerebri, through the tentorium cerebelli, or through the foramen magnum.
- #2 The Radiology Assistant : Systematic Approach to Brain Tumorshttps://radiologyassistant.nl/neuroradiology/brain-tumor/systematic-approach
Astrocytomas spread along the white matter tracts and do not respect the boundaries of the lobes. […] Because of this infiltrative growth, in many cases the tumor is actually larger than can be depicted with MR. […] Some tumors show subarachnoid seeding and form tumoral nodules along the brain and spinal cord. […] The ability of tumors to cross the midline limits the differential diagnosis. […] Glioblastoma multiforme (GBM) frequently crosses the midline by infiltrating the white matter tracts of the corpus callosum. […] Multiple tumors in the brain usually indicate metastatic disease. […] Primary brain tumors are typically seen in a single region, but some brain tumors like lymphomas, multicentric glioblastomas and gliomatosis cerebri can be multifocal. […] Most intra-axial tumors are located in the white matter.
- #2 Overview of Intracranial Tumors – Neurologic Disorders – Merck Manual Professional Editionhttps://www.merckmanuals.com/professional/neurologic-disorders/intracranial-and-spinal-tumors/overview-of-intracranial-tumors
Neurologic dysfunction may result from the following: […] A malignant tumor can develop new internal blood vessels, which can bleed or become occluded, resulting in necrosis and neurologic dysfunction that mimics stroke. […] Benign tumors grow slowly. They may become quite large before causing symptoms, partly because often there is no cerebral edema. Malignant primary tumors grow rapidly but rarely spread beyond the CNS. Death results from local tumor growth and/or tumor-related hemorrhage and thus can result from benign as well as malignant tumors.
- #2 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The persistent and aberrant activation of the NF-B signaling pathway is a hallmark of GBM. […] The Wnt signaling pathway is an ancient and fundamental genetic program that provides crucial regulatory instructions for cell growth, differentiation, and tissue patterning. […] The TGF- signaling pathway plays a crucial role in regulating key cellular processes, including proliferation, immune response, apoptosis, and adhesion. […] The MAPK signaling pathway plays a pivotal role in various cancers, including GBM, through its hyperactivation, which drives processes such as migration, proliferation, and survival. […] The p53 gene encodes a protein crucial for regulating cellular stress responses by controlling the expression of target genes involved in vital processes, including cell cycle regulation, apoptosis, differentiation, senescence, DNA repair, and neovascularization.
- #2 Signaling pathways in brain tumors and therapeutic interventions | Signal Transduction and Targeted Therapyhttps://www.nature.com/articles/s41392-022-01260-z
The vascular endothelial growth factor receptor (VEGFR) signaling pathway has been considered a key factor in GBM tumor survival. […] The transforming growth factor beta (TGF-) protein family has complicated functions in diverse regulatory pathways, where TGF-2 is a T cell inhibitor in the GBM tumor microenvironment that is found in approximately 90% of GBM tumor cells. […] Wingless and int-1 (Wnt) signaling modulates the neural progenitor cell (NPC) self-renewal, proliferation, as well as differentiation in the brain at varying stages of CNS development. […] The above crucial signaling pathways involved in glioma were demonstrated in Fig. 2.
- #2 Pathogenesis and Management of Brain Tumor-Related Epilepsy – Gliomas – NCBI Bookshelfhttps://www.ncbi.nlm.nih.gov/books/NBK570699/
Various animal and human tissue studies have identified glutamate, -aminobutyric acid (GABA), and adenosine kinase (ADK) as possible contributory factors for epileptogenesis in patients with brain tumors. Glioma studies in animals illustrated that seizure activity originated due to elevated glutamate production causing hyperexcitability around the peritumoral area. […] The genetic implications of BTRE are poorly understood. Genes such as LGI1 (a tumor-suppressor gene) and phosphatase and tensin homolog (PTEN) have been associated with gliomas and epilepsy; however, their exact role in epileptogenesis is not well characterized. The microenvironment and neurotransmission between peritumoral tissue and normal brain tissue is vastly different. Gliomas cause disruption of the blood-brain barrier in surrounding tissue by changing the endothelial permeability which can lead to vasogenic edema, inflammatory changes, poor perfusion, and changes in hemostasis. All these microenvironmental changes in peritumoral tissue can lead to sodium and calcium imbalance in the neuronal cells eventually causing hyperexcitability and seizures.
- #2 Immunotherapy for Brain Cancer – Cancer Research Institutehttps://www.cancerresearch.org/cancer-types/brain-cancer
Cancers of the brain and nervous system affect both adults and children, and come in several different forms. The cause of these cancers is not yet well understood. […] Glioblastoma (GBM), which forms from astrocytes, is the most dangerous and aggressive form of brain cancer. […] Despite significant advances in the understanding of brain cancer, and improvements to diagnosis, treatments, and patient quality of life, the mortality rate for brain cancer has remained consistent for more than three decades. […] New and developing brain cancer immunotherapies have the potential to reduce the harmful effects and improve survival rates for patients with brain cancer.
- #2 Why Do Brain Tumors Often Return After Treatment? MSK Researchers Say Stem Cells May Be Key | Memorial Sloan Kettering Cancer Centerhttps://www.mskcc.org/news/why-do-brain-tumors-often-return-after-treatment-msk-researchers-say-stem-cells-may-be-key
Glioblastoma brain tumors are one of the most deadly forms of cancer, with a five-year survival rate of less than 10% for patients 45 and older. Even when the tumors look as if they have been fully removed, they almost always come back. […] The standard therapy for glioblastoma targets actively dividing cells, says BTC Director Luis Parada, the papers senior author, who came to MSK in 2015 to develop a comprehensive program for fighting brain tumors. But here, we demonstrate the existence of a small percentage of dormant, stem-like cells that evade these therapies and reinitiate tumor development. […] Traditional chemotherapy and radiation therapy go after cells that are quickly growing and dividing a characteristic of most cancer cells. But in glioblastoma tumors, some cells are quiescent. That means they are essentially in a dormant, resting state hiding out from treatments aimed at cell division.
- #2 Why Do Brain Tumors Often Return After Treatment? MSK Researchers Say Stem Cells May Be Key | Memorial Sloan Kettering Cancer Centerhttps://www.mskcc.org/news/why-do-brain-tumors-often-return-after-treatment-msk-researchers-say-stem-cells-may-be-key
We found that quiescent cells very gradually give rise to dividing cells, which allow tumors to grow again, explains Dr. Parada, who is a member of the Cancer Biology and Genetics Program in the Sloan Kettering Institute. […] This research shows why therapies that focus only on cell division are insufficient for treating glioblastoma and reinforce the need for developing new strategies that target quiescent cells, Dr. Parada says. The discovery of activated cancer stem cells in mouse models provides us with unprecedented opportunity to investigate their unique features and self-renewal mechanisms, which will help in our ongoing efforts to find a cure for glioblastoma.
- #2 New Mechanism of Resistance Identified in Brain Tumorshttps://www.onclive.com/view/new-mechanism-of-resistance-identified-in-brain-tumors
Researchers have identified a mechanism that explains why patients with glioblastoma have not had successful outcomes when treated with inhibitors of mTOR despite the fact that it is overexpressed in approximately 90% of cases. […] Understanding the mechanisms of acquired resistance is essential for developing more effective treatments for patients that combine mTOR inhibitors with other agents to suppress this resistance, Mischel said. […] Investigations into these processes led Mischel and colleagues to study the relationship between mTOR and the promyelocytic leukemia (PML) gene. […] Mischel said that PML is able to suppress mTOR when mTOR levels are too high, making the cells quiescent in the process. […] Although the tumor cells grow more slowly, it enables the tumor to escape the treatment by rendering the tumor less dependent on the signal that you’re actually trying to target, Mischel said.
- #2 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugshttps://www.explorationpub.com/Journals/en/Article/100640
Brain metastasis is the most prevalent neurologic problem of systemic cancer and it can increase the mortality rate in patients with cancer. […] Significant interactions between cancer cells, the brain microenvironment, and the blood-brain barrier (BBB) play a major role in brain metastasis. […] There are significant impacts of ion channels in brain metastasis and cancer treatment failure. Targeting molecular mechanisms and ion channels in brain metastasis led to increasing the better response in these patients. […] The first stage of metastasis, known as EMT, is regulated by the plasma membrane and intracellular ion channels in cancer cells that have a high propensity for brain metastasis, such as lung and breast cancer. […] Research indicates that K+ and Cl channels play a role in gliomas and primary brain cancers.
- #2 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. […] Brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. […] The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. […] Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. […] Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation.
- #2 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a flexible role in the development of GBM, impacting both proliferation and metastasis. […] Hence, autophagy has the ability to control advancement of GBM. […] The role of autophagy in governing the advancement of glioma has been examined alongside GBM. […] Autophagy plays a two-fold role in controlling the advancement of glioma. […] Autophagy has also been extensively recorded in controlling the development of different brain tumors including medulloblastoma. […] The modulation of autophagy as a potential factor in the advancement of brain tumors and its manipulation (whether triggered or blocked) could be considered in the therapy for these malignancies. […] Autophagy is vital for the survival of tumor cells in the hypoxic glioma region and contributes to its aggressiveness.
- #2 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a crucial role in treating cancer by blocking the start of tumors and destroying cancer cells as they advance. […] Autophagy plays a role in regulating senescence and preventing cancer development. […] Autophagy is proposed as the primary factor in the cytotoxic effects of TMZ and inhibiting it significantly impacts TMZ’s anti-tumor effects in vitro. […] Autophagy plays a role in regulating drug resistance in brain tumors. […] There is growing evidence indicating that autophagy plays a role in regulating drug resistance in brain tumors. […] The failure to treat brain tumors is due to the ineffectiveness of conventional methods in causing cell death. […] The new therapeutics can be developed based on targeting autophagy for accelerating therapy and improving response to conventional therapeutics, including chemotherapy. […] Both promoting and blocking autophagy are proposed as potential therapies for brain tumors.
- #2 Brain tumor – Wikipediahttps://en.wikipedia.org/wiki/Brain_tumor
A brain tumor (sometimes referred more commonly as brain cancer) occurs when a group of cells within the brain turn cancerous and grow out of control, creating a mass. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cancerous) tumors. […] The cause of most brain tumors is unknown, though up to 4% of brain cancers may be caused by CT scan radiation. Uncommon risk factors include exposure to vinyl chloride, EpsteinBarr virus, ionizing radiation, and inherited syndromes such as neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau Disease. […] Mutations and deletions of tumor suppressor genes, such as P53, are thought to be the cause of some forms of brain tumor. Inherited conditions, such as Von HippelLindau disease, tuberous sclerosis, multiple endocrine neoplasia, and neurofibromatosis type 2 carry a high risk for the development of brain tumors.
- #3 The Radiology Assistant : Systematic Approach to Brain Tumorshttps://radiologyassistant.nl/neuroradiology/brain-tumor/systematic-approach
Astrocytomas spread along the white matter tracts and do not respect the boundaries of the lobes. […] Because of this infiltrative growth, in many cases the tumor is actually larger than can be depicted with MR. […] Some tumors show subarachnoid seeding and form tumoral nodules along the brain and spinal cord. […] The ability of tumors to cross the midline limits the differential diagnosis. […] Glioblastoma multiforme (GBM) frequently crosses the midline by infiltrating the white matter tracts of the corpus callosum. […] Multiple tumors in the brain usually indicate metastatic disease. […] Primary brain tumors are typically seen in a single region, but some brain tumors like lymphomas, multicentric glioblastomas and gliomatosis cerebri can be multifocal. […] Most intra-axial tumors are located in the white matter.
- #3 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The persistent and aberrant activation of the NF-B signaling pathway is a hallmark of GBM. […] The Wnt signaling pathway is an ancient and fundamental genetic program that provides crucial regulatory instructions for cell growth, differentiation, and tissue patterning. […] The TGF- signaling pathway plays a crucial role in regulating key cellular processes, including proliferation, immune response, apoptosis, and adhesion. […] The MAPK signaling pathway plays a pivotal role in various cancers, including GBM, through its hyperactivation, which drives processes such as migration, proliferation, and survival. […] The p53 gene encodes a protein crucial for regulating cellular stress responses by controlling the expression of target genes involved in vital processes, including cell cycle regulation, apoptosis, differentiation, senescence, DNA repair, and neovascularization.
- #3 Why Do Brain Tumors Often Return After Treatment? MSK Researchers Say Stem Cells May Be Key | Memorial Sloan Kettering Cancer Centerhttps://www.mskcc.org/news/why-do-brain-tumors-often-return-after-treatment-msk-researchers-say-stem-cells-may-be-key
Glioblastoma brain tumors are one of the most deadly forms of cancer, with a five-year survival rate of less than 10% for patients 45 and older. Even when the tumors look as if they have been fully removed, they almost always come back. […] The standard therapy for glioblastoma targets actively dividing cells, says BTC Director Luis Parada, the papers senior author, who came to MSK in 2015 to develop a comprehensive program for fighting brain tumors. But here, we demonstrate the existence of a small percentage of dormant, stem-like cells that evade these therapies and reinitiate tumor development. […] Traditional chemotherapy and radiation therapy go after cells that are quickly growing and dividing a characteristic of most cancer cells. But in glioblastoma tumors, some cells are quiescent. That means they are essentially in a dormant, resting state hiding out from treatments aimed at cell division.
- #3 Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities | Journal of Translational Medicine | Full Texthttps://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06063-0
Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. […] Brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. […] The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. […] Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. […] Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation.
- #4 Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies | Molecular Cancer | Full Texthttps://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02267-0
The persistent and aberrant activation of the NF-B signaling pathway is a hallmark of GBM. […] The Wnt signaling pathway is an ancient and fundamental genetic program that provides crucial regulatory instructions for cell growth, differentiation, and tissue patterning. […] The TGF- signaling pathway plays a crucial role in regulating key cellular processes, including proliferation, immune response, apoptosis, and adhesion. […] The MAPK signaling pathway plays a pivotal role in various cancers, including GBM, through its hyperactivation, which drives processes such as migration, proliferation, and survival. […] The p53 gene encodes a protein crucial for regulating cellular stress responses by controlling the expression of target genes involved in vital processes, including cell cycle regulation, apoptosis, differentiation, senescence, DNA repair, and neovascularization.