Przerzuty do mózgu – Patofizjologia i mechanizm

Przerzuty do mózgu
Patofizjologia i mechanizm

Przerzuty do mózgu, występujące u 20-40% pacjentów z nowotworami pierwotnymi, stanowią najczęstszy typ guzów wewnątrzczaszkowych i wiążą się z niekorzystnym rokowaniem. Proces przerzutowania jest wieloetapowy i obejmuje transformację komórek nowotworowych, ich migrację przez barierę krew-mózg (BBB) oraz adaptację do mikrośrodowiska mózgu. Przekroczenie BBB odbywa się głównie drogą paracelularną, z udziałem dysregulacji białek połączeń ścisłych (oklodyna, klaudyna-5, ZO-1) oraz enzymów proteolitycznych, takich jak katepsyna S, której inhibitor VBY-999 wykazuje potencjał terapeutyczny. Po kolonizacji mózgu komórki nowotworowe wykorzystują kooptację naczyniową i reprogramowanie metaboliczne (np. wzrost FABP7 i LEF1), co umożliwia im przetrwanie w warunkach hipoksji i niedoboru glukozy. Kluczową rolę w progresji przerzutów odgrywają także interakcje z komórkami gospodarza, w tym astrocytami, które poprzez produkcję TIMP1 modulują odpowiedź immunologiczną, hamując efektywność komórek obronnych. Wysokie poziomy lipokaliny-2 (LCN2) i białka S100A9 w przerzutach korelują z nasileniem neuroinflammacji, progresją choroby i gorszym rokowaniem, co wskazuje na ich potencjał jako biomarkerów i celów terapeutycznych.

Patogeneza przerzutów do mózgu

Bariera krew-mózg w procesie przerzutowania
Procesy po przekroczeniu bariery krew-mózg
Mechanizmy molekularne w przerzutach do mózgu

Pokonywanie bariery krew-mózg przez komórki nowotworowe

Transformacja nabłonkowo-mezenchymalna (EMT)
Rozkład macierzy zewnątrzkomórkowej i modyfikacja mikrośrodowiska
Rola zapalenia w procesie przerzutowania

Kolonizacja i wzrost w mózgu

Kooptacja naczyniowa
Reprogramowanie metaboliczne
Interakcje z mikrośrodowiskiem mózgu

Modulacja odporności i mikrośrodowiska w przerzutach do mózgu

Rola astrocytów w modulacji odpowiedzi immunologicznej
Markery prognostyczne i cele terapeutyczne
Znaczenie S100A9 w oporności na radioterapię

Implikacje kliniczne i potencjał terapeutyczny

Bariery w leczeniu przerzutów do mózgu
Celowanie w autofagię
Celowanie w lipokalinę-2
Kombinacja terapii dla przerzutów do mózgu
Kolejne rozdziały

Patogeneza przerzutów do mózgu

Przerzuty do mózgu stanowią najczęstszy rodzaj guzów wewnątrzczaszkowych u dorosłych i są związane z niekorzystnym rokowaniem. Częstość występowania przerzutów do mózgu wzrasta paradoksalnie wraz z rozwojem terapii celowanych, które poprawiają kontrolę choroby nowotworowej w środowisku pozaczaszkowym. Szacuje się, że 20-40% pacjentów z rozpoznanym pierwotnym nowotworem rozwinie przerzuty do mózgu.¹² Mechanizmy molekularne, które predysponują i ułatwiają rozwój przerzutów do mózgu, są słabo poznane, jednak zrozumienie tych procesów ma fundamentalne znaczenie dla lepszego zrozumienia rozwoju przerzutów i ostatecznie poprawy opieki nad pacjentem i zwiększenia przeżywalności.³

Patofizjologia przerzutów do mózgu to złożony, wieloetapowy proces, kierowany mechanizmami molekularnymi. Z pierwotnego narządu komórki nowotworowe muszą ulec transformacji, rozrastać się i być transportowane do ośrodkowego układu nerwowego, gdzie mogą pozostawać w stanie uśpienia przez różne okresy przed inwazją i dalszym wzrostem.⁴ Przerzuty do mózgu, podobnie jak do każdego innego narządu, wymagają złożonych sieci komunikacyjnych między komórką inwazyjną a komórkami rezydującymi w miejscu przerzutu. Przed przybyciem do miejsca przerzutu komórki nowotworowe mogą modulować mikrośrodowisko, aby uczynić je bardziej sprzyjającym przetrwaniu i wzrostowi. Hipoteza ta znana jest jako tworzenie niszy przedprzerzutowej.⁵

Bariera krew-mózg w procesie przerzutowania

Najbardziej unikalną barierą zapobiegającą przerzutom do mózgu jest istnienie bariery krew-mózg (BBB), ciągłego śródbłonka, który ściśle reguluje dostęp do mózgu. Aby komórki mogły przerzutować do mózgu, muszą pokonać tę barierę, co można osiągnąć przez zakłócenie integralności strukturalnej BBB.⁶ BBB reguluje transfer substancji chemicznych i rozpuszczalnych między układem krążenia a OUN, a jej unikalna struktura chroni OUN przed patogenami.⁷

Konkretna droga, którą komórki nowotworowe przekraczają BBB, pozostaje niejasna. Większość komórek nowotworowych wydaje się używać sposobu paracelularnego, podobnie jak komórki raka piersi przekraczające BBB, gdzie przeciskają się przez komórki śródbłonka, zaburzając ich połączenia międzykomórkowe. Co ciekawe, zakłócenie połączeń śródbłonka wydaje się być naprawiane po paracelularnej ekstrawazcji, bez znaczącego uszkodzenia BBB.⁸

Wysoce selektywna przepuszczalność BBB w dużej mierze zależy od obecności ciągłych połączeń ścisłych (tight junctions), które łączą komórki śródbłonka, co oznacza, że dysregulacja ekspresji białek połączeń ścisłych, takich jak oklodyna, klaudyna-5 i ZO-1, może krytycznie wpływać na przepuszczalność BBB. Proces ten może być wzmocniony przez substancję P wydzielaną z komórek raka piersi.⁹

Ponadto, katepsyna S wytwarzana przez komórki nowotworowe i makrofagi pośredniczy w transmigracji przez BBB poprzez proteolityczne przetwarzanie cząsteczki adhezji połączeń JAM-B, co dostarcza uzasadnienia dla stosowania specyficznego inhibitora katepsyny S – VBY-999 w redukcji eksperymentalnych przerzutów do mózgu.¹⁰

Procesy po przekroczeniu bariery krew-mózg

Po przekroczeniu bariery krew-mózg, mikrośrodowisko mózgu stwarza kolejne wyzwania dla wzrostu komórek nowotworowych. Mózg składa się z neuronów i komórek glejowych, które mogą podtrzymywać komórki nowotworowe poprzez przejęcie tego systemu wsparcia.¹¹ Komórki nowotworowe naciekające mózg muszą rozmnażać się w specyficznych warunkach metabolicznych, w szczególności w warunkach hipoksji i niedoboru glukozy.¹²

Gdy komórki nowotworowe opuszczą krwiobieg, rozpoczynają proces tworzenia kolonii przerzutowej. Kolonizacja przerzutów do mózgu obejmuje szereg kroków, w tym przebudzenie ze stanu uśpienia, kooptację naczyniową dla tworzenia mikroprzerzutów i reprogramowanie metaboliczne.¹³

Aktywne komórki przerzutowe mają tendencję do tworzenia mikroprzerzutów wzdłuż naczyń krwionośnych poprzez kooptację naczyniową, przygotowując się do ciągłego wzrostu zmian przerzutowych. Wykazano, że pomyślny wzrost komórek nowotworowych w mózgu wymaga przylegania do powierzchni naczyń włosowatych i rozciągania się w celu tworzenia wydłużonych skupisk wokół naczyń wraz z tworzeniem pętli naczyniowych.¹⁴

Brak kooptacji naczyniowej może spowodować niepowodzenie przerzutu, dlatego ingerencja w ten etap jest atrakcyjną strategią terapeutyczną. Zidentyfikowano różne kluczowe cząsteczki i komórki zaangażowane w promowanie kooptacji naczyniowej.¹⁵

Mechanizmy molekularne w przerzutach do mózgu

Dla stabilnej kolonizacji komórki nowotworowe muszą zmienić swój wzorzec metaboliczny, aby lepiej dostosować się do nowych mikrośrodowisk, w których się znajdują. Zwiększony poziom białka wiążącego kwasy tłuszczowe 7 (FABP7) w komórkach przerzutów do mózgu umożliwia im prosperowanie w nieprzyjaznych środowiskach poprzez wzmocniony efekt Warburga i wykorzystanie kwasów tłuszczowych.¹⁶

Czynnik transkrypcyjny LEF1 (lymphoid enhancer-binding factor-1) wspiera kolonizację przerzutową mózgu poprzez zwiększenie poziomu glutationu, aby hamować niszczenie komórek raka piersi przez reaktywne formy tlenu.¹⁷ Interakcje między komórkami raka a komórkami gospodarza wymagają dalszych badań; mogłyby być one rozważane jako potencjalne cele terapeutyczne dla poprawy skuteczności leczenia.¹⁸

Kanały jonowe są kluczowymi modulatorami patofizjologii komórek nowotworowych i są możliwymi celami leczenia raka. Projektując specyficzne nanomedykamenty dla kanałów jonowych zaangażowanych w raka mózgu, aktywność tych produktów może być kontrolowana w celu zmniejszenia lub zwiększenia wydajności. Opracowanie nanoleku do regulacji kanałów jonowych zaangażowanych w przerzuty do mózgu ma potencjał transformacji terapii raka i jest atrakcyjnym kierunkiem dalszych badań.¹⁹²⁰

Pokonywanie bariery krew-mózg przez komórki nowotworowe

Aby doszło do przerzutu, komórki nowotworowe muszą uzyskać dostęp do krążenia, przetrwać podczas cyrkulacji, przejść przez mikronaczynia adoptowanych organów, ekstrawiązać do miąższu narządu i ponownie osiedlić się w miejscu wtórnym. Proces ten wymaga, aby komórki nowotworowe przeniknęły przez błonę podstawną i przekroczyły błonę podśródbłonkową. Komórki nowotworowe osiągają to produkując enzymy proteolityczne, zwłaszcza metaloproteinazy i katepsyny, które pomagają im rozkładać macierz podstawną i zwiększać ich inwazyjność.²¹

Komórki nowotworowe modulują ekspresję fibronektyny, kolagenu lub lamininy oraz zmieniają typ receptora integrynowego na swojej powierzchni i na powierzchni otaczających komórek podścieliska, powodując dezintegrację komórek podścieliska i tworząc permisywne środowisko dla ich ekspansji i inwazji.²²

Wykazano, że komórki nowotworowe rekrutują komórki pochodzące ze szpiku kostnego w celu modyfikacji mikrośrodowiska odległego miejsca docelowego; tworzenie niszy przedprzerzutowej przez zmianę poziomu fibronektyny i uczynienie miejsca bardziej sprzyjającym kolonizacji przerzutowego guza.²³²⁴

Transformacja nabłonkowo-mezenchymalna (EMT)

Transformacja nabłonkowo-mezenchymalna (EMT), podobnie jak większość przerzutów, ma szczególne znaczenie i funkcję w przerzutach do mózgu. Wpływ EMT na proces przerzutowy i tworzenie mas przerzutowych wymaga dalszych badań, ale kilka badań wykazało przerzuty różnych nowotworów do mózgu poprzez aktywną rolę EMT w tym procesie.²⁵

EMT opisuje tymczasowe, odwracalne zjawisko, w którym komórki mogą ulegać odróżnicowaniu, migrować do odległego ogniska, a następnie ponownie różnicować się z powrotem do swojej oryginalnej komórki, tworząc nową strukturę.²⁶

Aby migrować, komórki zwykle przechodzą przejście nabłonkowo-mezenchymalne, złożony proces, w którym komórki nowotworowe pozbawiają się swoich cech nabłonkowych, stają się mniej zróżnicowane i mają bardziej agresywne i podobne do komórek macierzystych cechy. EMT zachodzi podczas lokalnej inwazji i intrawazcji.²⁷

Rozkład macierzy zewnątrzkomórkowej i modyfikacja mikrośrodowiska

Zdolność komórek nowotworowych do ucieczki z miejsca pierwotnego zależy od ich zdolności do przebudowy macierzy zewnątrzkomórkowej (ECM). Kompleks molekularny E-kadheryna-katenina jest niezbędny do utrzymania normalnej i nowotworowej cytoarchitektury.²⁸

Komórki przerzutowe wytwarzają enzymy proteolityczne, które mogą degradować błonę podstawną nabłonka (BM), która pełni ważną funkcję w utrzymaniu BBB. Komórki inwazyjne przyczepiają się do komórek śródbłonka mikronaczyń w mózgu i lizują komórki BM, następnie komórki inwazyjne wnikają do krążenia ogólnego i inwazyjnie wnikają do BBB.²⁹

W przerzutach do mózgu występują zmiany molekularne w blaszce podstawnej mikronaczyń, a dowody wskazują, że przepuszczalność naczyń krwionośnych zwiększa się. W przerzutach do mózgu komórki nowotworowe inwazyjnie wnikają do BBB i zwiększają przepuszczalność komórek śródbłonka związanych z guzem.³⁰

Rola zapalenia w procesie przerzutowania

Guz może przyciągać komórki zapalne, które zapewniają bardziej korzystne warunki dla dalszego wzrostu przerzutów i wpływają na BBB. Podczas rozwoju guza przerzutowego w mózgu jego objętość zwiększa się, a on sam nacieka tkankę mózgową pod wpływem czynników wzrostu wytwarzanych przez astrocyty.³¹

W nowym badaniu z Uniwersytetu w Tel Awiwie opublikowanym w czasopiśmie Nature Cancer, zespół badaczy kierowany przez prof. Netę Erez, szefa laboratorium biologii guzów z Zakładu Patologii na Wydziale Medycyny Sacklera, zidentyfikował i scharakteryzował nowy mechanizm, który ułatwia tworzenie przerzutów do mózgu i stwierdził, że upośledzenie tego mechanizmu znacząco zmniejszyło rozwój przerzutów do mózgu u myszy.³²

W tym nowym badaniu badacze wykazali, że lipokalina-2 (LCN2) jest kluczowym czynnikiem wywołującym stan zapalny neurologiczny w mózgu. Co więcej, badacze odkryli, że wysokie poziomy LCN2 we krwi pacjentów i przerzutach do mózgu z kilku typów raka są związane z progresją choroby i zmniejszoną przeżywalnością.³³

„Nasze odkrycia ujawniają wcześniej nieznany mechanizm, w którym LCN2 pośredniczy w komunikacji między komórkami odpornościowymi ze szpiku kostnego a komórkami podporowymi w mózgu, aktywuje mechanizmy zapalne i w ten sposób pomaga w progresji choroby przerzutowej w mózgu, i zademonstrowane jego znaczenie”.³⁴

Kolonizacja i wzrost w mózgu

Gdy komórki nowotworowe opuszczą krwiobieg, rozpoczynają proces zakładania kolonii przerzutowej. Kolonizacja komórek przerzutowych w mózgu obejmuje szereg kroków, w tym przebudzenie ze stanu uśpienia, kooptację naczyniową dla tworzenia mikroprzerzutów i reprogramowanie metaboliczne.³⁵

Kooptacja naczyniowa

Po przejściu BBB, CTCs docierają do miąższu mózgu. Warunkiem wstępnym udanej kolonizacji miąższu jest ustanowienie niszy przerzutowej opartej na interakcjach z kilkoma typami komórek.³⁷ Kolonizacja mózgu przez komórki nowotworowe jest wynikiem wzajemnych interakcji z mikrośrodowiskiem guza. Jedną z konsekwentnych cech obserwowanych w tym kontekście jest nabywanie fenotypu neuronalnego w oparciu o przeprogramowanie transkrypcyjne.³⁸

Brak kooptacji naczyniowej może spowodować niepowodzenie przerzutu; dlatego ingerencja w ten etap jest atrakcyjną strategią terapeutyczną. Zidentyfikowano różne kluczowe cząsteczki i komórki zaangażowane w promowanie kooptacji naczyniowej.³⁹

Reprogramowanie metaboliczne

Komórki nowotworowe naciekające mózg muszą rozmnażać się w specyficznych warunkach metabolicznych, w szczególności w warunkach hipoksji i niedoboru glukozy.⁴² Warunki hipoksyczne tworzące się w nekrotycznej części centralnej guzów przerzutowych przyczyniają się również do ich niestabilności genetycznej.⁴³

Interakcje z mikrośrodowiskiem mózgu

Interakcje między komórkami nowotworowymi a komórkami gospodarza wymagają dalszych badań; mogłyby one być rozważane jako potencjalne cele terapeutyczne dla poprawy skuteczności leczenia.⁴⁴

Środowisko międzykomórkowe, w tym komórki śródbłonka, perycyty, fibroblasty i leukocyty, przyczynia się do stresów na komórki nowotworowe, zwiększając niestabilność genomową i dysregulację epigenetyczną.⁴⁵⁴⁶

Badacze z CNIO odkryli, że rak wypacza pewne komórki mózgowe, astrocyty, i powoduje, że wytwarzają one białko, które działa na korzyść guza. „Odkryliśmy, wyjaśnia Neibla Priego, pierwszy autor pracy, że pewne komórki mózgowe zwane astrocytami działają jako immunomodulatory, to znaczy wchodzą w interakcje z układem odpornościowym w mózgu, a w przypadkach przerzutów do mózgu nadużywają tej funkcji, ponieważ są pod wpływem guza”.⁴⁷

Wypaczone w ten sposób przez raka, astrocyty sprzymierzają się z komórkami nowotworowymi, gdy dochodzi do przerzutów do mózgu. Interakcja astrocytów z układem odpornościowym, która powinna być normalnym procesem immunomodulacji, staje się mechanizmem, który napędza raka, ponieważ astrocyty zakłócają pracę komórek obronnych i uniemożliwiają im zabijanie komórek nowotworowych.⁴⁸

Grupa CNIO zidentyfikowała kluczową cząsteczkę w tym procesie, zwaną TIMP1. „Astrocyty pro-nowotworowe produkują TIMP1, a to białko jest zaangażowane w dezaktywację komórek obronnych, które powinny zabijać komórki nowotworowe”, mówi Priego.⁴⁹

Modulacja odporności i mikrośrodowiska w przerzutach do mózgu

Przerzuty do mózgu są wynikiem złożonych interakcji między komórkami nowotworowymi, mikrośrodowiskiem mózgu i układem odpornościowym gospodarza. Zrozumienie tych interakcji jest kluczowe dla opracowania skutecznych strategii terapeutycznych.

Rola astrocytów w modulacji odpowiedzi immunologicznej

Grupa badawcza CNIO zidentyfikowała kluczową rolę astrocytów w modulacji odpowiedzi immunologicznej w przerzutach do mózgu. Badacze odkryli, że pewne komórki mózgowe zwane astrocytami działają jako immunomodulatory, to znaczy wchodzą w interakcje z układem odpornościowym w mózgu, a w przypadkach przerzutów do mózgu nadużywają tej funkcji, ponieważ są pod wpływem guza.⁵⁰

Markery prognostyczne i cele terapeutyczne

Wykazawszy, że cząsteczka TIMP1 działa na komórki układu odpornościowego i czyni je mniej skutecznymi, zespół CNIO proponuje wykorzystanie jej jako biomarkera do wykrywania przerzutów do mózgu dotkniętych tym immunosupresyjnym mechanizmem. Badanie idzie dalej. Grupa Manuela Valiente proponuje alternatywę terapeutyczną ukierunkowaną na astrocyty: połączenie immunoterapii z inhibitorami, które zapobiegają produkcji cząsteczki TIMP1.⁵³

Celem jest połączenie inhibicji TIMP1 z tradycyjną immunoterapią, „co zwiększyłoby siłę strategii terapeutycznej i ułatwiło jej włączenie do protokołów klinicznych”, mówi Valiente.⁵⁴

Lipokalina-2 (LCN2) została zidentyfikowana jako kluczowy czynnik wywołujący neuroinflammację w mózgu. Badacze odkryli, że wysokie poziomy LCN2 we krwi pacjentów i przerzutach do mózgu z kilku typów raka są związane z progresją choroby i zmniejszoną przeżywalnością. „Wykazaliśmy znaczenie LCN2 dla rozwoju przerzutów poprzez genetyczne hamowanie jego ekspresji u myszy, co spowodowało znaczne zmniejszenie neuroinflammacji i zmniejszenie przerzutów do mózgu”.⁵⁵⁵⁶

Znaczenie S100A9 w oporności na radioterapię

Poprzez bezstronną analizę eksperymentalnych modeli in vivo przerzutów do mózgu opornych na WBRT, zidentyfikowano aktywację szlaku S100A9-RAGE-NF-kB-JunB w przerzutach do mózgu jako potencjalnego mediatora oporności w tym narządzie.⁵⁷

Badacze odkryli, że komórki nowotworowe z przerzutami do mózgu z różnych guzów pierwotnych są indukowane do wysokiej ekspresji S100A9 w środowisku mózgu, co pośredniczy w oporności na radioterapię poprzez aktywację NF-kB.⁵⁸

Genetyczne lub farmakologiczne celowanie w S100A9 przez przepuszczalny przez barierę krew-mózg inhibitor FPS-ZM1 jego receptora, RAGE (receptor dla zaawansowanych produktów glikacji), silnie uwrażliwia przerzuty do mózgu na napromienianie w eksperymentalnych modelach przerzutów do mózgu, a także w organotypowych hodowlach pochodzących od pacjentów.⁵⁹

Wyniki badaczy sugerują wykorzystanie S100A9 jako klinicznie istotnego biomarkera do personalizacji radioterapii dla pacjentów z przerzutami do mózgu oraz inhibitora FPS-ZM1 jako środka radiouczulającego.⁶⁰

Implikacje kliniczne i potencjał terapeutyczny

Zrozumienie patogenezy przerzutów do mózgu ma kluczowe znaczenie dla opracowania skutecznych strategii terapeutycznych. Wiele badań koncentruje się obecnie na celowaniu w konkretne mechanizmy molekularne zaangażowane w proces przerzutowania.

Bariery w leczeniu przerzutów do mózgu

Jedną z głównych przeszkód w leczeniu przerzutów do mózgu jest bariera krew-mózg (BBB), która ogranicza przenikanie wielu leków do tkanki mózgowej. Większość leków nie przenika efektywnie przez barierę krew-mózg i to jest jeden z głównych powodów, dla których przerzuty do mózgu są tak trudne do leczenia.⁶¹

Hydroksychlorochina hamuje autofagię w późniejszym punkcie szlaku i, co ważne, łatwo przenika przez barierę krew-mózg. Badacze wykazali, że ta kombinacja leków skutecznie zmniejszyła liczbę i rozmiar przerzutów raka piersi do mózgu w modelach mysich.⁶²

Celowanie w autofagię

Badanie prowadzone przez badaczy z University of Arizona Cancer Center zidentyfikowało mechanizm biologiczny, który może prowadzić do bardziej skutecznych metod leczenia raka piersi, który uległ przerzutom do mózgu. Badając różnice metaboliczne między pierwotnymi komórkami raka piersi a tymi, które ulegają przerzutom do mózgu, ustalili, że autofagia była znacznie zwiększona w przerzutach do mózgu. Autofagia jest procesem recyklingu komórkowego, który komórki nowotworowe mogą wykorzystywać do przetrwania w stresujących warunkach, takich jak te wywołane przez leki przeciwnowotworowe.⁶³

„Byliśmy w stanie zakłócić zdolność komórek raka piersi do tworzenia przerzutów do mózgu poprzez upośledzenie szlaku autofagii.” W badaniu opublikowanym w Clinical and Translational Medicine badacze najpierw pokazali, że ukierunkowanie na kluczowy gen regulujący autofagię ATG7 znacznie zmniejszyło zdolność komórek raka piersi do tworzenia przerzutów do mózgu w modelach mysich.⁶⁴

Celowanie w lipokalinę-2

Badacze z Uniwersytetu w Tel Awiwie zidentyfikowali i scharakteryzowali nowy mechanizm, który ułatwia tworzenie przerzutów do mózgu i odkryli, że upośledzenie tego mechanizmu znacząco zmniejszyło rozwój przerzutów do mózgu u myszy. W tym badaniu badacze wykazali, że lipokalina-2 (LCN2) jest kluczowym czynnikiem wywołującym neuroinflammację w mózgu. Ponadto odkryli, że wysokie poziomy LCN2 we krwi pacjentów i przerzutach do mózgu z kilku typów raka są związane z progresją choroby i zmniejszoną przeżywalnością.⁶⁵

„Wykazaliśmy znaczenie LCN2 dla rozwoju przerzutów poprzez genetyczne hamowanie jego ekspresji u myszy, co spowodowało znaczne zmniejszenie neuroinflammacji i zmniejszenie przerzutów do mózgu. Funkcjonalne i prognostyczne aspekty LCN2, które zidentyfikowaliśmy w przerzutach do mózgu w modelach mysich, a także u pacjentów z rakiem, sugerują, że celowanie w LCN2 mogłoby być skuteczną strategią terapeutyczną opóźniającą lub zapobiegającą nawrotowi przerzutów do mózgu.”⁶⁶

Kombinacja terapii dla przerzutów do mózgu

Badanie prowadzone przez Ludwig Cancer Research zidentyfikowało i wstępnie zwalidowało kombinowane leczenie przerzutów do mózgu raka piersi, częstej i zazwyczaj śmiertelnej manifestacji złośliwości. Kombinowana terapia, opisana w bieżącym numerze Nature Cancer, celuje w związane z guzem makrofagi i mikroglej (TAM), komórki odpornościowe znajdowane w przerzutach do mózgu, które komórki nowotworowe mogą manipulować, aby wspierać ich wzrost i przeżycie.⁶⁷

Mechanizm ten, który angażuje alternatywny szlak sygnalizacyjny w TAM skupiony wokół wydzielanego czynnika białkowego o nazwie CSF2 i białka, które pomaga przekazywać jego sygnały, STAT5, ożywia wzrost guza poprzez promowanie ekspresji genów zaangażowanych w zapalenie i gojenie ran.⁶⁸

Badacze pokazują, że blokowanie tego szlaku sygnalizacyjnego w połączeniu z inhibicją CSF1R znacząco wydłuża przeżycie w modelach mysich przerzutów z piersi do mózgu. „Nasze badanie identyfikuje racjonalnie opracowaną terapię kombinowaną, która angażuje przeciwnowotworową odpowiedź immunologiczną i jednocześnie podważa mechanizm oporności, który, jak teraz wykazaliśmy, może rozwinąć się w odpowiedzi na początkową terapię, inhibicję CSF1R.”⁶⁹

Badacze z CNIO zaproponowali nową metodę leczenia przerzutów do mózgu, które słabo reagują, lub wcale, na immunoterapię, i dostarczyli biomarker do przewidywania, w których przypadkach powinna być stosowana. Dla przerzutów do mózgu – gdy guz, który rozpoczął się w innym narządzie, rozprzestrzenia się do mózgu – niedawno próbowano immunoterapii, z mieszanymi wynikami.⁷⁰

Grupa CNIO zidentyfikowała kluczową cząsteczkę w procesie, zwaną TIMP1. „Pro-tumorowe astrocyty produkują TIMP1, a to białko jest zaangażowane w dezaktywację komórek obronnych, które powinny zabijać komórki nowotworowe”. Po wykazaniu, że ta cząsteczka, TIMP1, działa na komórki układu odpornościowego i czyni je mniej skutecznymi, zespół CNIO proponuje wykorzystanie jej jako biomarkera do wykrywania przerzutów do mózgu dotkniętych tym immunosupresyjnym mechanizmem.⁷¹

„TIMP1 jest dobrym biomarkerem, ponieważ jest wydzielany w znacznie większych ilościach w płynie mózgowo-rdzeniowym pacjentów z przerzutami do mózgu”, mówi Priego. Grupa Manuela Valiente proponuje alternatywę terapeutyczną ukierunkowaną na astrocyty: połączenie immunoterapii z inhibitorami, które zapobiegają produkcji cząsteczki TIMP1.⁷²

„Istnieje lek zwany silibininą, który jest już stosowany na zasadzie użycia ze względów humanitarnych, który hamuje produkcję cząsteczki TIMP1”, mówi Valiente. „Trwa już badanie kliniczne w celu przetestowania jego skuteczności terapeutycznej w przerzutach do mózgu. Mamy nadzieję, że będziemy mieć wyniki w 2025 roku.”⁷³

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

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

Materiały źródłowe

#1 Brain Metastasis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1157902-overview
Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body. Metastatic tumors are among the most common mass lesions in the brain. It is estimated that 20%40% of all patients diagnosed with a primary cancer will develop a secondary cancer in the brain. […] To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade. […] Cancer cells have been shown to recruit bone marrowderived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor.
#2 Molecular Mechanisms Driving the Formation of Brain Metastases
https://www.mdpi.com/2072-6694/14/19/4963
Brain metastases are the most common brain tumor in adults and are associated with poor prognosis. […] The molecular mechanisms that predispose and facilitate brain metastasis development are poorly understood. […] The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sites of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. […] Metastasis to the brain, like any organ, requires complex communication networks between the invading cell and resident cells of the metastasis location. Before arrival at the site of metastasis, tumor cells can modulate the microenvironment to be more conducive of survival and outgrowth. This hypothesis is known as the formation of the pre-metastatic niche.
#3 Molecular Mechanisms Driving the Formation of Brain Metastases
https://www.mdpi.com/2072-6694/14/19/4963
Brain metastases are the most common brain tumor in adults and are associated with poor prognosis. […] The molecular mechanisms that predispose and facilitate brain metastasis development are poorly understood. […] The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sites of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. […] Metastasis to the brain, like any organ, requires complex communication networks between the invading cell and resident cells of the metastasis location. Before arrival at the site of metastasis, tumor cells can modulate the microenvironment to be more conducive of survival and outgrowth. This hypothesis is known as the formation of the pre-metastatic niche.
#4 Brain metastases: epidemiology and pathophysiology – PubMed
https://pubmed.ncbi.nlm.nih.gov/16215811/
Metastases are the most common tumors of the central nervous system (CNS), but cancer databases are often incomplete leading to underestimation of the incidence of even symptomatic brain metastases. […] The pathophysiology of brain metastases is a complex multistage process, mediated by molecular mechanisms; from the primary organ, cancer cells must transform, grow and be transported to the CNS where they can lay dormant for various lengths of time before invading and growing further. […] Understanding the pathophysiology of brain metastases is of great importance, because it may lead to the development of more efficient therapies to combat brain tumor growth or to possibly make the CNS an undesirable environment for tumor progression.
#5 Molecular Mechanisms Driving the Formation of Brain Metastases
https://www.mdpi.com/2072-6694/14/19/4963
Brain metastases are the most common brain tumor in adults and are associated with poor prognosis. […] The molecular mechanisms that predispose and facilitate brain metastasis development are poorly understood. […] The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sites of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. […] Metastasis to the brain, like any organ, requires complex communication networks between the invading cell and resident cells of the metastasis location. Before arrival at the site of metastasis, tumor cells can modulate the microenvironment to be more conducive of survival and outgrowth. This hypothesis is known as the formation of the pre-metastatic niche.
#6 Molecular Mechanisms Driving the Formation of Brain Metastases
https://www.mdpi.com/2072-6694/14/19/4963
Perhaps the most unique barrier preventing metastasis of the brain is the existence of the bloodâbrain barrier (BBB), a continuous endothelium which tightly regulates access to the brain. In order for cells to metastasize to the brain, they must cross this barrier, which can be achieved by disruption of the structural integrity of the BBB. […] Once tumor cells have passed the BBB, the brain microenvironment presents further challenges to their growth. […] Tumor cells invading the brain need to propagate under specific metabolic conditions, in particular conditions of hypoxia and glucose shortage. […] Whether brain metastases were molecularly similar to the primary tumors from which they arise was largely unknown until recently with the evolution of technology such as next-generation sequencing.
#7 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
In brain metastasis, there are molecular changes in the basal lamina of the microvessels and evidence indicates that the permeability of blood vessels increases. […] The BBB regulates the transfer of chemicals and solutes between the circulatory system and the CNS and its unique structure protect the CNS against pathogens. […] In brain metastases, tumor cells invade BBB and increased permeability of tumor-associated endothelial cells. […] Ion channels are crucial modulators of the pathophysiology of cancer cells. […] Ion channels are therefore possible targets for cancer treatment. […] Targeting ion channels in cancer treatment is attractive and effective but their functions in normal cells should be considered and blocking their abilities have enormous side effects too. […] The use of nanomedicines and new methods in drug delivery can be a breakthrough in this field.
#8 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The specific route by which tumour cells cross the BBB remains unclear. […] Most cancer cells seem to use a paracellular mode, just as BC cells crossing BBB, whereby they squeeze through ECs by disrupting their intercellular junctions. […] Interestingly, the disruption to EC junctions seems to be repaired after paracellular extravasation, without significant damage to the BBB. […] Components of the BBB can also be directly targeted by several factors during the process of BCBM. […] The highly selective permeability of the BBB largely depends on the presence of continuous TJs that connect ECs, and so it follows that dysregulation of the expression of TJ proteins, such as occludin, claudin-5 and ZO-1, can critically influence BBB permeability. […] This process can be enhanced by substance P secreted from BC cells.
#9 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The specific route by which tumour cells cross the BBB remains unclear. […] Most cancer cells seem to use a paracellular mode, just as BC cells crossing BBB, whereby they squeeze through ECs by disrupting their intercellular junctions. […] Interestingly, the disruption to EC junctions seems to be repaired after paracellular extravasation, without significant damage to the BBB. […] Components of the BBB can also be directly targeted by several factors during the process of BCBM. […] The highly selective permeability of the BBB largely depends on the presence of continuous TJs that connect ECs, and so it follows that dysregulation of the expression of TJ proteins, such as occludin, claudin-5 and ZO-1, can critically influence BBB permeability. […] This process can be enhanced by substance P secreted from BC cells.
#10 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
Moreover, cathepsin S generated by tumour cells and macrophages mediates BBB transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B, providing a rationale for the use of the cathepsin S-specific inhibitor VBY-999 in reducing experimental brain metastasis. […] Once the cancer cells have exited the bloodstream, they begin the process of founding a metastatic colony. […] The colonisation of BCBM cells includes a series of steps, including reawakening from dormancy state, vascular co-option for micrometastases formation, and metabolic reprogramming. […] Active metastatic cells tend to form micrometastases along blood vessels through vascular co-option, preparing for continuous growth of metastatic lesions. […] The successful growth of tumour cells in the brain has been shown to require adhesion to the surface of capillaries and stretching to form elongated clusters around the vessels along with capillary loop formation.
#11 Molecular Mechanisms Driving the Formation of Brain Metastases
https://pmc.ncbi.nlm.nih.gov/articles/PMC9563727/
Perhaps the most unique barrier preventing metastasis of the brain is the existence of the blood-brain barrier (BBB), a continuous endothelium which tightly regulates access to the brain. In order for cells to metastasize to the brain, they must cross this barrier, which can be achieved by disruption of the structural integrity of the BBB. […] Once tumor cells have passed the BBB, the brain microenvironment presents further challenges to their growth. The brain consists of neurons and glial cells which can sustain the tumor cells by hijacking this support system. […] Tumor cells invading the brain need to propagate under specific metabolic conditions, in particular conditions of hypoxia and glucose shortage. […] Despite the absence of genomic alterations associated with BM in the study by Fukumura, identifiable gene mutations in BM generally provide insights into shared gene alterations which are common across brain metastases.
#12 Molecular Mechanisms Driving the Formation of Brain Metastases
https://www.mdpi.com/2072-6694/14/19/4963
Perhaps the most unique barrier preventing metastasis of the brain is the existence of the bloodâbrain barrier (BBB), a continuous endothelium which tightly regulates access to the brain. In order for cells to metastasize to the brain, they must cross this barrier, which can be achieved by disruption of the structural integrity of the BBB. […] Once tumor cells have passed the BBB, the brain microenvironment presents further challenges to their growth. […] Tumor cells invading the brain need to propagate under specific metabolic conditions, in particular conditions of hypoxia and glucose shortage. […] Whether brain metastases were molecularly similar to the primary tumors from which they arise was largely unknown until recently with the evolution of technology such as next-generation sequencing.
#13 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
Moreover, cathepsin S generated by tumour cells and macrophages mediates BBB transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B, providing a rationale for the use of the cathepsin S-specific inhibitor VBY-999 in reducing experimental brain metastasis. […] Once the cancer cells have exited the bloodstream, they begin the process of founding a metastatic colony. […] The colonisation of BCBM cells includes a series of steps, including reawakening from dormancy state, vascular co-option for micrometastases formation, and metabolic reprogramming. […] Active metastatic cells tend to form micrometastases along blood vessels through vascular co-option, preparing for continuous growth of metastatic lesions. […] The successful growth of tumour cells in the brain has been shown to require adhesion to the surface of capillaries and stretching to form elongated clusters around the vessels along with capillary loop formation.
#14 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
Moreover, cathepsin S generated by tumour cells and macrophages mediates BBB transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B, providing a rationale for the use of the cathepsin S-specific inhibitor VBY-999 in reducing experimental brain metastasis. […] Once the cancer cells have exited the bloodstream, they begin the process of founding a metastatic colony. […] The colonisation of BCBM cells includes a series of steps, including reawakening from dormancy state, vascular co-option for micrometastases formation, and metabolic reprogramming. […] Active metastatic cells tend to form micrometastases along blood vessels through vascular co-option, preparing for continuous growth of metastatic lesions. […] The successful growth of tumour cells in the brain has been shown to require adhesion to the surface of capillaries and stretching to form elongated clusters around the vessels along with capillary loop formation.
#15 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#16 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#17 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#18 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#19 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
In brain metastasis, there are molecular changes in the basal lamina of the microvessels and evidence indicates that the permeability of blood vessels increases. […] The BBB regulates the transfer of chemicals and solutes between the circulatory system and the CNS and its unique structure protect the CNS against pathogens. […] In brain metastases, tumor cells invade BBB and increased permeability of tumor-associated endothelial cells. […] Ion channels are crucial modulators of the pathophysiology of cancer cells. […] Ion channels are therefore possible targets for cancer treatment. […] Targeting ion channels in cancer treatment is attractive and effective but their functions in normal cells should be considered and blocking their abilities have enormous side effects too. […] The use of nanomedicines and new methods in drug delivery can be a breakthrough in this field.
#20 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
By designing specific nanomedicines for ion channels involved in brain cancer, the activity of these products can be controlled to reduce or increase performance. […] 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.
#21 Brain Metastasis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1157902-overview
Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body. Metastatic tumors are among the most common mass lesions in the brain. It is estimated that 20%40% of all patients diagnosed with a primary cancer will develop a secondary cancer in the brain. […] To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade. […] Cancer cells have been shown to recruit bone marrowderived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor.
#22 Brain Metastasis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1157902-overview
Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body. Metastatic tumors are among the most common mass lesions in the brain. It is estimated that 20%40% of all patients diagnosed with a primary cancer will develop a secondary cancer in the brain. […] To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade. […] Cancer cells have been shown to recruit bone marrowderived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor.
#23 Brain Metastasis: Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1157902-overview
Brain metastases are cancer cells that have spread to the brain from primary tumors in other organs in the body. Metastatic tumors are among the most common mass lesions in the brain. It is estimated that 20%40% of all patients diagnosed with a primary cancer will develop a secondary cancer in the brain. […] To metastasize, tumor cells have to gain access to the circulation, survive while circulating, pass through the microvasculature of the adopted organs, extravasate into the organ parenchyma, and reestablish themselves at the secondary site. This process requires the tumor cells to penetrate the basement membrane and cross the subendothelial membrane. Tumor cells achieve this by producing proteolytic enzymes, particularly metalloproteinases and cathepsins to help them to break down the basal matrix and enhance their invasiveness. Tumor cells modulate the expression of fibronectin, collagen, or laminin, and change the type of integrin receptor on their surface and on the surface of the surrounding stromal cells, resulting in desegregation of the stromal cells and creating a permissive environment for them to expand and invade. […] Cancer cells have been shown to recruit bone marrowderived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor.
#24 Brain Metastases – Dr. Prem Pillay | Singapore
https://singaporebrain.org/en/brain/brain-metastases/
Additionally, cancer cells recruit bone marrow-derived cells to modify the microenvironment of distant recipient sites, forming a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor. […] Cancer cells have been shown to recruit bone marrow-derived cells to modify the microenvironment of distant recipient site; the formation of a premetastatic niche by alternating the level of fibronectin and making the site more favorable for the colonization of metastatic tumor.
#25 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
The capacity of tumor cells for evading has derived from changes in inhibitors and growth suppressor factors of cell proliferation in different mechanisms. […] Metastatic cells produce proteolytic enzymes that can degrade the epithelial basement membrane (BM) which has an important function in maintaining the BBB. […] Invader cells attach to the microvessel endothelial cells in the brain and lyse the BM cells then invader cells penetrate to the body circulation and invade the BBB. […] EMT, like most metastases, has a special importance and function in brain metastasis. […] The impacts of EMT on the metastatic process and establishing metastatic masses need more investigation but several studies showed the metastases of different cancers to the brain via the active role of EMT in this incidence.
#26 Intracerebral metastases pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Intracerebral_metastases_pathophysiology
The epithelial-mesenchymal transition (EMT) describes a temporary, reversible phenomenon wherein cells can dedifferentiate, migrate to a distant focus, and then redifferentiate back to their original cell, forming a new structure. […] Progression in cancer also involves activating a number of cells in the adjacent stroma via paracrine signaling. […] Once the phenotypically aggressive clone has developed, spread of the tumor consists of a series of two sequential steps: namely, invasion of the extracellular matrix (ECM) with penetration into the vasculature and hematogenous dissemination to the central nervous system. […] The E-cadherin-catenin molecular complex is essential to maintain a normal and tumoral cytoarchitecture. […] The ability of tumor cells to escape the primary site is dependent on their ability to remodel the ECM.
#27 Breaking boundaries: role of the brain barriers in metastatic process | Fluids and Barriers of the CNS | Full Text
https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-025-00618-z
To migrate, cells usually undergo epithelial-mesenchymal transition (EMT), a complex process in which cancer cells shed their epithelial characteristics, become less differentiated, and have more aggressive and stem cell-like characteristics. […] EMT occurs during local invasion and intravasation. […] In the case of BMs, CTCs must extravasate and cross the bloodbrain barrier (BBB) by breaching the tight junctions (TJs) between endothelial cells in brain capillaries. […] This involves the secretion of proteases and the activation of pathways that disrupt the integrity of the BBB. […] The BBB is perhaps the major reason for the high incidence of BMs since many therapeutic compounds cannot penetrate the barrier, lowering treatment efficiency. […] It is crucial to better understand the mechanisms of the interaction of tumor cells with the BBB to find druggable targets to prevent or at least limit BM formation. […] The major pathological processes involved in the transfer of metastatic cells through brain barriers include the upregulation of adhesion molecules, proteolytic enzymes, trophic factors, and neuroinflammatory changes.
#28 Intracerebral metastases pathophysiology – wikidoc
https://www.wikidoc.org/index.php/Intracerebral_metastases_pathophysiology
The epithelial-mesenchymal transition (EMT) describes a temporary, reversible phenomenon wherein cells can dedifferentiate, migrate to a distant focus, and then redifferentiate back to their original cell, forming a new structure. […] Progression in cancer also involves activating a number of cells in the adjacent stroma via paracrine signaling. […] Once the phenotypically aggressive clone has developed, spread of the tumor consists of a series of two sequential steps: namely, invasion of the extracellular matrix (ECM) with penetration into the vasculature and hematogenous dissemination to the central nervous system. […] The E-cadherin-catenin molecular complex is essential to maintain a normal and tumoral cytoarchitecture. […] The ability of tumor cells to escape the primary site is dependent on their ability to remodel the ECM.
#29 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
The capacity of tumor cells for evading has derived from changes in inhibitors and growth suppressor factors of cell proliferation in different mechanisms. […] Metastatic cells produce proteolytic enzymes that can degrade the epithelial basement membrane (BM) which has an important function in maintaining the BBB. […] Invader cells attach to the microvessel endothelial cells in the brain and lyse the BM cells then invader cells penetrate to the body circulation and invade the BBB. […] EMT, like most metastases, has a special importance and function in brain metastasis. […] The impacts of EMT on the metastatic process and establishing metastatic masses need more investigation but several studies showed the metastases of different cancers to the brain via the active role of EMT in this incidence.
#30 Brain metastasis from the perspective of molecular mechanisms and treatment, presenting a new approach for targeting ion channels by nano drugs
https://www.explorationpub.com/Journals/en/Article/100640
In brain metastasis, there are molecular changes in the basal lamina of the microvessels and evidence indicates that the permeability of blood vessels increases. […] The BBB regulates the transfer of chemicals and solutes between the circulatory system and the CNS and its unique structure protect the CNS against pathogens. […] In brain metastases, tumor cells invade BBB and increased permeability of tumor-associated endothelial cells. […] Ion channels are crucial modulators of the pathophysiology of cancer cells. […] Ion channels are therefore possible targets for cancer treatment. […] Targeting ion channels in cancer treatment is attractive and effective but their functions in normal cells should be considered and blocking their abilities have enormous side effects too. […] The use of nanomedicines and new methods in drug delivery can be a breakthrough in this field.
#31 The Mechanism of Development of Brain Metastases | Radiology Key
https://radiologykey.com/the-mechanism-of-development-of-brain-metastases/
The tumor can attract inflammatory cells that provide more favorable conditions for a further growth of metastases and affect the BBB. […] During the development of a metastatic tumor in the brain, its volume increases, and it invades into the brain tissue underdriven by growth factors produced by astrocytes.
#32 Mechanism facilitates brain metastasis from breast cancer and melanoma by inducing neuroinflammation
https://medicalxpress.com/news/2023-02-mechanism-brain-metastasis-breast-cancer.html
In a new study from Tel Aviv University published in the journal Nature Cancer, a team of researchers led by Prof. Neta Erez, head of the laboratory for the biology of tumors from the Department of Pathology at the Sackler Faculty of Medicine, identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in mice. […] Brain metastases are one of the deadliest forms of cancer metastasis. They are 2â10 times more common than tumors of the central nervous system (CNS). Despite the progress achieved in recent years in the development of novel treatments for melanoma and breast cancer, brain metastasis remain highly lethal with grave survival rates of less than one year in many cases.
#33 Mechanism facilitates brain metastasis from breast cancer and melanoma by inducing neuroinflammation
https://medicalxpress.com/news/2023-02-mechanism-brain-metastasis-breast-cancer.html
In this new study from the Tel Aviv University, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. […] Prof. Neta Erez says, „Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.” […] „We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.” […] „We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance.”
#34 Mechanism facilitates brain metastasis from breast cancer and melanoma by inducing neuroinflammation
https://medicalxpress.com/news/2023-02-mechanism-brain-metastasis-breast-cancer.html
In this new study from the Tel Aviv University, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. […] Prof. Neta Erez says, „Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.” […] „We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.” […] „We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance.”
#35 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
Moreover, cathepsin S generated by tumour cells and macrophages mediates BBB transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B, providing a rationale for the use of the cathepsin S-specific inhibitor VBY-999 in reducing experimental brain metastasis. […] Once the cancer cells have exited the bloodstream, they begin the process of founding a metastatic colony. […] The colonisation of BCBM cells includes a series of steps, including reawakening from dormancy state, vascular co-option for micrometastases formation, and metabolic reprogramming. […] Active metastatic cells tend to form micrometastases along blood vessels through vascular co-option, preparing for continuous growth of metastatic lesions. […] The successful growth of tumour cells in the brain has been shown to require adhesion to the surface of capillaries and stretching to form elongated clusters around the vessels along with capillary loop formation.
#36 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
Moreover, cathepsin S generated by tumour cells and macrophages mediates BBB transmigration through proteolytic processing of the junctional adhesion molecule, JAM-B, providing a rationale for the use of the cathepsin S-specific inhibitor VBY-999 in reducing experimental brain metastasis. […] Once the cancer cells have exited the bloodstream, they begin the process of founding a metastatic colony. […] The colonisation of BCBM cells includes a series of steps, including reawakening from dormancy state, vascular co-option for micrometastases formation, and metabolic reprogramming. […] Active metastatic cells tend to form micrometastases along blood vessels through vascular co-option, preparing for continuous growth of metastatic lesions. […] The successful growth of tumour cells in the brain has been shown to require adhesion to the surface of capillaries and stretching to form elongated clusters around the vessels along with capillary loop formation.
#37 Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention | Cancer Genomics & Proteomics
https://cgp.iiarjournals.org/content/13/4/245
Since there are no lymphatic vessels in the brain, circulating tumor cells (CTCs) reach the brain via the hematogenous route and have to surpass the BBB as a prerequisite for homing, colonization and outgrowth in the brain parenchyma. The BBB is a neurovascular unit acting as a gatekeeper and restricts the entrance of macromolecules into the brain. […] In order to colonize the brain parenchyma, CTCs have to traverse brain endothelial cells, a process referred to as transendothelial migration. […] After passage of the BBB, CTCs reach the brain parenchyma. A prerequisite for successful colonization of the parenchyma is the establishment of a metastatic niche based on interactions with several types of cells as outlined in the following chapters. […] Colonization of the brain with tumor cells is the result of reciprocal interactions with the tumor microenvironment. One of the consistent features observed in this context is the acquisition of a neuronal phenotype based on transcriptional reprograming, as outlined below.
#38 Dissection of the Process of Brain Metastasis Reveals Targets and Mechanisms for Molecular-based Intervention | Cancer Genomics & Proteomics
https://cgp.iiarjournals.org/content/13/4/245
Since there are no lymphatic vessels in the brain, circulating tumor cells (CTCs) reach the brain via the hematogenous route and have to surpass the BBB as a prerequisite for homing, colonization and outgrowth in the brain parenchyma. The BBB is a neurovascular unit acting as a gatekeeper and restricts the entrance of macromolecules into the brain. […] In order to colonize the brain parenchyma, CTCs have to traverse brain endothelial cells, a process referred to as transendothelial migration. […] After passage of the BBB, CTCs reach the brain parenchyma. A prerequisite for successful colonization of the parenchyma is the establishment of a metastatic niche based on interactions with several types of cells as outlined in the following chapters. […] Colonization of the brain with tumor cells is the result of reciprocal interactions with the tumor microenvironment. One of the consistent features observed in this context is the acquisition of a neuronal phenotype based on transcriptional reprograming, as outlined below.
#39 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#40 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#41 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#42 Molecular Mechanisms Driving the Formation of Brain Metastases
https://pmc.ncbi.nlm.nih.gov/articles/PMC9563727/
Perhaps the most unique barrier preventing metastasis of the brain is the existence of the blood-brain barrier (BBB), a continuous endothelium which tightly regulates access to the brain. In order for cells to metastasize to the brain, they must cross this barrier, which can be achieved by disruption of the structural integrity of the BBB. […] Once tumor cells have passed the BBB, the brain microenvironment presents further challenges to their growth. The brain consists of neurons and glial cells which can sustain the tumor cells by hijacking this support system. […] Tumor cells invading the brain need to propagate under specific metabolic conditions, in particular conditions of hypoxia and glucose shortage. […] Despite the absence of genomic alterations associated with BM in the study by Fukumura, identifiable gene mutations in BM generally provide insights into shared gene alterations which are common across brain metastases.
#43 :: BTRT :: Brain Tumor Research and Treatment
https://btrt.org/DOIx.php?id=10.14791/btrt.2022.0045
The clonal selection hypothesis suggests that metastatic cancer cells are selected toward an appropriate phenotype for cancer metastasis and chromosomal instability contributes to the development of this metastatic clone. […] Hypoxic conditions formed in the necrotic central portion of metastatic tumors also contribute to their genetic instability. […] The intercellular milieu, including endothelial cells, pericytes, fibroblasts, and leukocytes, contributes to stresses on the tumor cells, enhancing genomic instability and epigenetic dysregulation. […] MicroRNAs have been highlighted for their contributions to important adaptive post-translational modifications in cancer development, metastasis, and therapeutic resistance. […] The tumor-platelet interaction has been linked with fibrin production and ensuing hypercoagulability in cancer patients.
#44 Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies | British Journal of Cancer
https://www.nature.com/articles/s41416-021-01424-8
The absence of vascular co-option can cause a failure of metastasis; thus, interfering with this step is an attractive therapeutic strategy. […] Various key molecules and cells that are involved in promoting vascular co-option have been identified. […] For stable colonisation to occur, tumour cells need to alter their metabolic pattern to better adapt to the new microenvironments in which they find themselves. […] An increased level of fatty-acid-binding protein 7 (FABP7) in BCBM cells enables them to thrive in hostile environments through an enhanced Warburg effect and fatty-acid utilisation. […] The transcription factor lymphoid enhancer-binding factor-1 (LEF1) supports brain metastatic colonisation by boosting the levels of glutathione to hinder ROS-mediated destruction in epithelial BC cells. […] The interactions between BC cells and host cells merits further investigation; they could be considered as potential therapy targets for improving treatment efficacy.
#45 :: BTRT :: Brain Tumor Research and Treatment
https://www.btrt.org/DOIx.php?id=10.14791/btrt.2022.0045
The clonal selection hypothesis suggests that metastatic cancer cells are selected toward an appropriate phenotype for cancer metastasis and chromosomal instability contributes to the development of this metastatic clone. […] The authors suggested that these genetic variations stem from the complex molecular landscape and microenvironment of metastatic cancers. […] The intercellular milieu, including endothelial cells, pericytes, fibroblasts, and leukocytes, contributes to stresses on the tumor cells, enhancing genomic instability and epigenetic dysregulation. […] MicroRNAs have been highlighted for their contributions to important adaptive post-translational modifications in cancer development, metastasis, and therapeutic resistance. […] The microRNA profile changes in metastatic tumor cells compared with those of primary tumors have been reported for many different cancer types.
#46 :: BTRT :: Brain Tumor Research and Treatment
https://btrt.org/DOIx.php?id=10.14791/btrt.2022.0045
The clonal selection hypothesis suggests that metastatic cancer cells are selected toward an appropriate phenotype for cancer metastasis and chromosomal instability contributes to the development of this metastatic clone. […] Hypoxic conditions formed in the necrotic central portion of metastatic tumors also contribute to their genetic instability. […] The intercellular milieu, including endothelial cells, pericytes, fibroblasts, and leukocytes, contributes to stresses on the tumor cells, enhancing genomic instability and epigenetic dysregulation. […] MicroRNAs have been highlighted for their contributions to important adaptive post-translational modifications in cancer development, metastasis, and therapeutic resistance. […] The tumor-platelet interaction has been linked with fibrin production and ensuing hypercoagulability in cancer patients.
#47 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
CNIO researchers have discovered that cancer perverts certain brain cells, the astrocytes, and causes them to produce a protein that works in favour of the tumour. […] We have discovered, explains Neibla Priego, first author of the paper, that certain brain cells called astrocytes act as immunomodulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse this function because they are being influenced by the tumour. […] Perverted in this way by cancer, astrocytes ally with tumour cells when brain metastasis occurs. The interaction of astrocytes with the immune system, which should be a normal process of immunomodulation, becomes a mechanism that fuels cancer, because astrocytes interfere with the work of defence cells and prevent them from killing tumour cells.
#48 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
CNIO researchers have discovered that cancer perverts certain brain cells, the astrocytes, and causes them to produce a protein that works in favour of the tumour. […] We have discovered, explains Neibla Priego, first author of the paper, that certain brain cells called astrocytes act as immunomodulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse this function because they are being influenced by the tumour. […] Perverted in this way by cancer, astrocytes ally with tumour cells when brain metastasis occurs. The interaction of astrocytes with the immune system, which should be a normal process of immunomodulation, becomes a mechanism that fuels cancer, because astrocytes interfere with the work of defence cells and prevent them from killing tumour cells.
#49 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
The CNIO group has identified a key molecule in the process, called TIMP1. Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells, says Priego. […] Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. […] The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule. […] There is a drug called silibinin, which has already been employed on a compassionate use basis, which inhibits the production of the TIMP1 molecule, says Valiente.
#50 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
CNIO researchers have discovered that cancer perverts certain brain cells, the astrocytes, and causes them to produce a protein that works in favour of the tumour. […] We have discovered, explains Neibla Priego, first author of the paper, that certain brain cells called astrocytes act as immunomodulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse this function because they are being influenced by the tumour. […] Perverted in this way by cancer, astrocytes ally with tumour cells when brain metastasis occurs. The interaction of astrocytes with the immune system, which should be a normal process of immunomodulation, becomes a mechanism that fuels cancer, because astrocytes interfere with the work of defence cells and prevent them from killing tumour cells.
#51 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
CNIO researchers have discovered that cancer perverts certain brain cells, the astrocytes, and causes them to produce a protein that works in favour of the tumour. […] We have discovered, explains Neibla Priego, first author of the paper, that certain brain cells called astrocytes act as immunomodulators, that is, they interact with the immune system in the brain, and in cases of brain metastasis they misuse this function because they are being influenced by the tumour. […] Perverted in this way by cancer, astrocytes ally with tumour cells when brain metastasis occurs. The interaction of astrocytes with the immune system, which should be a normal process of immunomodulation, becomes a mechanism that fuels cancer, because astrocytes interfere with the work of defence cells and prevent them from killing tumour cells.
#52 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
The CNIO group has identified a key molecule in the process, called TIMP1. Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells, says Priego. […] Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. […] The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule. […] There is a drug called silibinin, which has already been employed on a compassionate use basis, which inhibits the production of the TIMP1 molecule, says Valiente.
#53 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
The CNIO group has identified a key molecule in the process, called TIMP1. Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells, says Priego. […] Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. […] The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule. […] There is a drug called silibinin, which has already been employed on a compassionate use basis, which inhibits the production of the TIMP1 molecule, says Valiente.
#54 CNIO researchers propose a new treatment for brain metastasis|ERC
https://erc.europa.eu/news-events/news/cnio-researchers-propose-new-treatment-brain-metastasis
The goal is to combine TIMP1 inhibition with traditional immunotherapy, which would increase the potency of the therapeutic strategy and facilitate its incorporation into clinical protocols, says Valiente. […] Our research is not only innovative from a clinical point of view, but also very useful for the advancement of scientific knowledge, says Valiente.
#55 Mechanism facilitates brain metastasis from breast cancer and melanoma by inducing neuroinflammation
https://medicalxpress.com/news/2023-02-mechanism-brain-metastasis-breast-cancer.html
In this new study from the Tel Aviv University, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. […] Prof. Neta Erez says, „Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target.” […] „We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. Moreover, in blood and tissue samples from patients with brain metastases from three types of cancer, blood LCN2 levels were correlated with disease progression and with shorter survival, which positions LCN2 as a potential prognostic marker for brain metastases.” […] „We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance.”
#56 Researchers Discover Mechanism that Facilitates Formation of Brain Metastases | Tel Aviv University | Tel Aviv University
https://english.tau.ac.il/lcn2_brain_metastases
We show that signals secreted into the blood from the primary tumor stimulate pro-inflammatory activation of astrocytes in the brain. The astrocytes promote the recruitment of inflammatory cells from the bone marrow (granulocytes) into the brain, and they in turn become a main source of signaling by LCN2. […] We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. […] Prof. Erez adds: „We analyzed the LCN2 protein levels in the blood and cerebrospinal fluid (CSF) of mice with brain metastases and found that LCN2 levels increased greatly in mice with melanoma and breast cancer metastases compared to healthy mice. […] The researchers also examined whether LCN2 is elevated in the blood of melanoma patients at the time of initial diagnosis, and whether it can be a prognostic factor. […] We have identified a new mechanism in which LCN2 mediates the communication between immune cells from the bone marrow and supporting cells in the brain, activates inflammatory mechanisms and thus helps the progression of metastatic disease in the brain, and demonstrated its importance.
#57 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism | Nature Medicine
https://www.nature.com/articles/s41591-022-01749-8
Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. […] Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. […] Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9RAGE-NF-B-JunB pathway in brain metastases as a potential mediator of resistance in this organ.
#58 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism | Nature Medicine
https://www.nature.com/articles/s41591-022-01749-8
Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. […] Here, we report that brain metastatic cancer cells from different primary tumors are induced to highly express S100A9 within the brain microenvironment, which mediates resistance to radiotherapy by downstream activation of NF-B. […] Genetic or pharmacological targeting of S100A9 by the blood-brain barrier-permeable inhibitor FPS-ZM1 of its receptor, RAGE (receptor for advanced glycation end products), potently sensitizes brain metastasis to irradiation in experimental models of brain metastasis as well as in patient-derived organotypic cultures. […] Thus, our data suggest that S100A9 expression is induced in cancer cells under specific contexts correlating with the acquisition of radioresistance.
#59 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism | Nature Medicine
https://www.nature.com/articles/s41591-022-01749-8
Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. […] Here, we report that brain metastatic cancer cells from different primary tumors are induced to highly express S100A9 within the brain microenvironment, which mediates resistance to radiotherapy by downstream activation of NF-B. […] Genetic or pharmacological targeting of S100A9 by the blood-brain barrier-permeable inhibitor FPS-ZM1 of its receptor, RAGE (receptor for advanced glycation end products), potently sensitizes brain metastasis to irradiation in experimental models of brain metastasis as well as in patient-derived organotypic cultures. […] Thus, our data suggest that S100A9 expression is induced in cancer cells under specific contexts correlating with the acquisition of radioresistance.
#60 Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism | Nature Medicine
https://www.nature.com/articles/s41591-022-01749-8
Our findings suggest the use of S100A9 as a clinically relevant biomarker to personalize radiotherapy for patients with brain metastasis and the inhibitor FPS-ZM1 as a radiosensitizing agent. […] Our results, together with recent data, suggest that the acquisition of therapeutic resistance in brain metastasis might be linked to the induction of cellular plasticity mechanisms activated by the crosstalk with the microenvironment during colonization. […] Thus, S100A9 should be considered as a biomarker to predict therapeutic response of brain metastases to WBRT. […] In summary, we report a comprehensive strategy that not only identifies patients who could benefit from WBRT but also provide a combination therapy to overcome radioresistance.
#61 Study identifies potential pathway to reducing breast cancer brain metastases | The University of Arizona Health Sciences
https://healthsciences.arizona.edu/news/releases/study-identifies-potential-pathway-reducing-breast-cancer-brain-metastases
Hydroxychloroquine inhibits autophagy at a later point in the pathway and, importantly, readily crosses the blood-brain barrier. […] Most drugs do not efficiently cross the blood-brain barrier, and that is one of the key reasons why brain metastases are so difficult to treat. […] They showed that this drug combination successfully reduced the number and size of breast cancer brain metastases in mouse models. […] Carew said the team was amazed by how significantly they were able to diminish the ability of breast cancer cells to form brain metastases by targeting a single pathway. […] Our group and others have shown that activation of autophagy makes it harder for many different types of cancer therapies to kill cancer cells and this promotes drug resistance. […] Brain metastases are the most prevalent adult central nervous system tumors, with 20% to 30% of cases resulting from breast cancer patients, particularly those with triple negative and HER2 amplified disease. Managing breast cancer metastases in the brain is challenging, with only 20% of patients with breast cancer brain metastases surviving beyond five years.
#62 Study identifies potential pathway to reducing breast cancer brain metastases | The University of Arizona Health Sciences
https://healthsciences.arizona.edu/news/releases/study-identifies-potential-pathway-reducing-breast-cancer-brain-metastases
Hydroxychloroquine inhibits autophagy at a later point in the pathway and, importantly, readily crosses the blood-brain barrier. […] Most drugs do not efficiently cross the blood-brain barrier, and that is one of the key reasons why brain metastases are so difficult to treat. […] They showed that this drug combination successfully reduced the number and size of breast cancer brain metastases in mouse models. […] Carew said the team was amazed by how significantly they were able to diminish the ability of breast cancer cells to form brain metastases by targeting a single pathway. […] Our group and others have shown that activation of autophagy makes it harder for many different types of cancer therapies to kill cancer cells and this promotes drug resistance. […] Brain metastases are the most prevalent adult central nervous system tumors, with 20% to 30% of cases resulting from breast cancer patients, particularly those with triple negative and HER2 amplified disease. Managing breast cancer metastases in the brain is challenging, with only 20% of patients with breast cancer brain metastases surviving beyond five years.
#63 Study identifies potential pathway to reducing breast cancer brain metastases | The University of Arizona Health Sciences
https://healthsciences.arizona.edu/news/releases/study-identifies-potential-pathway-reducing-breast-cancer-brain-metastases
A study led by researchers from the University of Arizona Cancer Center at UArizona Health Sciences identified a biological mechanism that could lead to more effective treatments for breast cancer that has metastasized to the brain. […] By studying the metabolic differences between primary breast cancer cells and those that metastasize to the brain, they determined that autophagy was significantly upregulated in brain metastases. Autophagy is a cellular recycling process that cancer cells can use to stay alive when faced with stressful conditions such as those triggered by anticancer drugs. […] We were able to disrupt breast cancer cells ability to form brain metastases by impairing the autophagy pathway. […] In the study published in Clinical and Translational Medicine, the researchers first showed that targeting the key autophagy regulating gene ATG7 significantly reduced the ability of breast cancer cells to form brain metastases in mouse models.
#64 Study identifies potential pathway to reducing breast cancer brain metastases | The University of Arizona Health Sciences
https://healthsciences.arizona.edu/news/releases/study-identifies-potential-pathway-reducing-breast-cancer-brain-metastases
A study led by researchers from the University of Arizona Cancer Center at UArizona Health Sciences identified a biological mechanism that could lead to more effective treatments for breast cancer that has metastasized to the brain. […] By studying the metabolic differences between primary breast cancer cells and those that metastasize to the brain, they determined that autophagy was significantly upregulated in brain metastases. Autophagy is a cellular recycling process that cancer cells can use to stay alive when faced with stressful conditions such as those triggered by anticancer drugs. […] We were able to disrupt breast cancer cells ability to form brain metastases by impairing the autophagy pathway. […] In the study published in Clinical and Translational Medicine, the researchers first showed that targeting the key autophagy regulating gene ATG7 significantly reduced the ability of breast cancer cells to form brain metastases in mouse models.
#65 Researchers Discover Mechanism that Facilitates Formation of Brain Metastases | Tel Aviv University | Tel Aviv University
https://english.tau.ac.il/lcn2_brain_metastases
Brain metastases are one of the deadliest forms of cancer metastasis, with grave survival rates of less than one year in many cases. […] In a new study from Tel Aviv University, researchers identified and characterized a new mechanism that facilitates the formation of brain metastases and found that impairing this mechanism significantly reduced the development of brain metastases in lab models. […] In this new study, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. […] Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases.
#66 TAU researchers successfully reduce brain metastases in mice – The Jerusalem Post
https://www.jpost.com/health-and-wellness/article-732284
IN THIS NEW STUDY, the researchers show that Lipocalin-2 (LCN2) is a key factor in inducing neuroinflammation in the brain. Moreover, the researchers found that high LCN2 levels in patients’ blood and brain metastases from several types of cancer are associated with disease progression and reduced survival. […] Our findings reveal a previously unknown mechanism, mediated by LCN2, which reveals a central role for the mutual interactions between immune cells recruited to the brain (granulocytes) and brain glial cells (astrocytes) in promoting inflammation and in the formation of brain metastases, Erez said. The findings establish LCN2 as a new prognostic marker and a potential therapeutic target. […] We demonstrated the importance of LCN2 for the development of metastases by genetically inhibiting its expression in mice, which resulted in a significant decrease in neuroinflammation and reduced brain metastases. […] The functional and prognostic aspects of LCN2 that we have identified in brain metastases in mouse models as well as in cancer patients suggest that targeting LCN2 could be an effective therapeutic strategy to delay or prevent the recurrence of brain metastases.
#67 Study identifies potential combination therapy for brain metastases of breast cancer – ecancer
https://ecancer.org/en/news/21119-study-identifies-potential-combination-therapy-for-brain-metastases-of-breast-cancer
Study identifies potential combination therapy for brain metastases of breast cancer. A Ludwig Cancer Research study has identified and pre-clinically validated combination treatments for the brain metastases of breast cancer, a common and typically lethal manifestation of the malignancy. The combination therapy, reported in the current issue of Nature Cancer, targets tumour-associated macrophages and microglia (TAMs), immune cells found within brain metastases that cancer cells can manipulate to support their growth and survival. […] That mechanism, which engages an alternative signalling pathway in TAMs centred on a secreted protein factor named CSF2 and a protein that helps transmit its signals, STAT5, revives tumour growth by promoting the expression of genes involved in inflammation and wound repair.
#68 Study identifies potential combination therapy for brain metastases of breast cancer – ecancer
https://ecancer.org/en/news/21119-study-identifies-potential-combination-therapy-for-brain-metastases-of-breast-cancer
Study identifies potential combination therapy for brain metastases of breast cancer. A Ludwig Cancer Research study has identified and pre-clinically validated combination treatments for the brain metastases of breast cancer, a common and typically lethal manifestation of the malignancy. The combination therapy, reported in the current issue of Nature Cancer, targets tumour-associated macrophages and microglia (TAMs), immune cells found within brain metastases that cancer cells can manipulate to support their growth and survival. […] That mechanism, which engages an alternative signalling pathway in TAMs centred on a secreted protein factor named CSF2 and a protein that helps transmit its signals, STAT5, revives tumour growth by promoting the expression of genes involved in inflammation and wound repair.
#69 Study identifies potential combination therapy for brain metastases of breast cancer – ecancer
https://ecancer.org/en/news/21119-study-identifies-potential-combination-therapy-for-brain-metastases-of-breast-cancer
The researchers show that blocking this signalling pathway in concert with CSF1R inhibition significantly extends survival in mouse models of breast-to-brain metastases. […] Our study identifies a rationally-devised combination therapy that engages an anti-cancer immune response and simultaneously undermines a resistance mechanism that, we have now shown, can develop in response to the initial therapy, CSF1R inhibition. […] Over the long term, the treatment also triggered adaptive changes in TAMs that drive inflammation and resulted in damage to neural tissue around the brain metastases. […] Subsequent analysis revealed that TAMs had compensated for the blockade of CSF1R signalling by engaging an alternative signalling axis switched on by the related CSF2 receptor (CSF2R) and mediated by STAT5 within the cells.
#70 Azthena logo with the word Azthena
https://www.news-medical.net/news/20241002/New-treatment-proposed-for-brain-metastases-resistant-to-immunotherapy.aspx
Researchers at the Spanish National Cancer Research Centre (CNIO) propose a new treatment for brain metastases that respond poorly, or not at all, to immunotherapy, and provide a biomarker to predict in which cases it should be used. […] For brain metastasis – when a tumor that started in another organ spreads to the brain – immunotherapy has recently been tried, with mixed results. […] „Brain metastasis poses a serious clinical problem,” explains Manuel Valiente, head of the CNIO Brain Metastasis Group and director of the study whose results are now being published. „Patients with advanced brain metastases, that is, those who can already perceive symptoms of metastases, don’t respond well to immunotherapy. But even patients who respond well to immunotherapy increasingly relapse, often because of new metastases in the brain.”
#71 Azthena logo with the word Azthena
https://www.news-medical.net/news/20241002/New-treatment-proposed-for-brain-metastases-resistant-to-immunotherapy.aspx
The CNIO group has identified a key molecule in the process, called TIMP1. „Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells,” says Priego. […] Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. […] „TIMP1 is a good biomarker, because it is secreted in significantly higher amounts in the cerebrospinal fluid of patients with brain metastases,” says Priego. […] The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.
#72 Azthena logo with the word Azthena
https://www.news-medical.net/news/20241002/New-treatment-proposed-for-brain-metastases-resistant-to-immunotherapy.aspx
The CNIO group has identified a key molecule in the process, called TIMP1. „Pro-tumour astrocytes produce TIMP1, and this protein is involved in disabling the defensive cells that should kill cancer cells,” says Priego. […] Having demonstrated that this molecule, TIMP1, acts on immune system cells and renders them less effective, the CNIO team proposes to use it as a biomarker to detect brain metastases affected by this immunosuppressive mechanism. […] „TIMP1 is a good biomarker, because it is secreted in significantly higher amounts in the cerebrospinal fluid of patients with brain metastases,” says Priego. […] The study goes further. Manuel Valiente’s group proposes a therapeutic alternative that targets astrocytes: the combination of immunotherapy with inhibitors that prevent the production of the TIMP1 molecule.
#73 Azthena logo with the word Azthena
https://www.news-medical.net/news/20241002/New-treatment-proposed-for-brain-metastases-resistant-to-immunotherapy.aspx
„There is a drug called silibinin, which has already been employed on a compassionate use basis, which inhibits the production of the TIMP1 molecule,” says Valiente. „A clinical trial is already underway to test its therapeutic efficacy in brain metastasis. We hope to have the results in 2025.” […] The goal is to combine TIMP1 inhibition with traditional immunotherapy, „which would increase the potency of the therapeutic strategy and facilitate its incorporation into clinical protocols,” says Valiente. […] „Until now, astrocytes have not been considered as immunomodulators, either in general studies or in relation to brain tumors. Our research is not only innovative from a clinical point of view, but also very useful for the advancement of scientific knowledge,” says Valiente.