Estratégia potencial para o tratamento do câncer de fígado: estudo descobre via de sinalização mediada por vesículas extracelulares
Uma equipe de pesquisa liderada pela Professora Judy Yam Wai-ping do Departamento de Patologia da Escola de Medicina Clínica da Faculdade de Medicina LKS da Universidade de Hong Kong (HKUMed) fez um avanço significativo ao revelar uma via...
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)
Os SEVs circulantes de pacientes com CHC promovem a angiogênese in vitro e in vivo. A) Ensaio de formação de tubo de HUVECs pré-tratados com PBS, sEVs circulantes de indivíduos controle (normais) (n = 3) e pacientes com CHC em estágio inicial (E-HCC) (n = 3) e estágio tardio (L-HCC) (n = 4). B) HUVECs pré-tratadas com os sEVs indicados foram submetidas a um ensaio de brotamento endotelial. C) Diagrama esquemático do ensaio Matrigel in vivo. Células PLC/PRF/5 foram co-injetadas subcutaneamente com PBS, normal, E-HCC ou L-HCC-sEVs (n = 5 ou 15 camundongos no total). D) Imunohistoquímica de tumores excisados ??com coloração CD31 indicando formação de microvasos. A quantificação dos microvasos é mostrada. São mostradas imagens representativas da coloração CD31 e uma imagem ampliada da região na caixa inserida. Barra de escala: 100 ?m. Os dados são apresentados como média ± SEM. *P < 0,05, **P < 0,01; ***P < 0,001. P < 0,05 foi considerado estatisticamente significativo. NS, não significativo. Crédito:Ciência Avançada (2023). DOI: 10.1002/advs.202302677
Uma equipe de pesquisa liderada pela Professora Judy Yam Wai-ping do Departamento de Patologia da Escola de Medicina Clínica da Faculdade de Medicina LKS da Universidade de Hong Kong (HKUMed) fez um avanço significativo ao revelar uma via de sinalização não reconhecida mediada pela circulação de pequenos vesículas extracelulares (sEVs) derivadas de pacientes com câncer de fígado que promovem metástase de câncer de fígado. Esta descoberta apresenta uma estratégia terapêutica potencial para o tratamento do câncer de fígado. As descobertas foram publicadas na Advanced Science .
O câncer de fígado é o quinto câncer mais comum e a terceira principal causa de morte por câncer em Hong Kong. Como um tumor hipervascular, o câncer de fígado é em grande parte impulsionado pela modulação de pequenas vesículas extracelulares derivadas de tumor (sEVs) dentro do microambiente tumoral.
A vascularização aprimorada permite que células tumorais entrem na corrente sanguínea, facilitando sua disseminação para locais distantes e, portanto, metástase do câncer. Evidências crescentes sugerem que os sEVs derivados de tumores desempenham um papel na modulação da sinalização angiogênica. Compreender os mecanismos pelos quais os SEVs regulam a angiogênese no câncer de fígado poderia levar ao desenvolvimento de novas estratégias terapêuticas.
O perfil proteômico de sEVs circulantes de indivíduos controle e indivíduos com Carcinoma Hepatocelular (CHC) (o tipo mais comum de câncer primário de fígado) revelou que o fator de von Willibrand (vWF) é regulado positivamente progressivamente ao longo dos estágios de desenvolvimento do câncer de fígado. A elevação drástica do nível de sEV-vWF em pacientes com CHC indicou sua potencialidade como marcador diagnóstico não invasivo para câncer de fígado. A equipe de pesquisa também mostrou que a capacidade de indução de sEVs circulantes de pacientes em estágio avançado no desenvolvimento de câncer de fígado e a metástase foi atenuada pelo anticorpo anti-vWF, demonstrando o papel crucial do sEV-vWF no câncer de fígado.
Os sEVs enriquecidos com vWF derivados de células de câncer de fígado exibiram um efeito promotor significativo na angiogênese, na adesão endotelial do tumor e na permeabilidade vascular. Os fatores de crescimento liberados pelas células endoteliais poderiam, por sua vez, promover o crescimento e a motilidade das células cancerígenas. O estudo revela uma estimulação mútua não reconhecida entre células tumorais e endoteliais iniciada por sEV-vWF. Usando um modelo de câncer de fígado em camundongos, a equipe observou que a angiogênese aumentada mediada pelo sEV-vWF facilita o desenvolvimento do câncer de fígado e metástase à distância, o que é crucial para o desenvolvimento e metástase do câncer de fígado.
A equipe demonstrou ainda que o tratamento combinado de Sorafenibe (o tratamento padrão de primeira linha para pacientes com câncer de fígado avançado de fígado avançado), com anticorpo anti-vWF ou o inibidor pan-FGFR Erdafitinibe, melhorou significativamente o resultado do tratamento do que o tratamento isolado com Sorafenibe em pacientes derivados. modelo de rato xenoenxertado. Os resultados sugeriram uma nova abordagem terapêutica para o câncer de fígado, bloqueando a comunicação intercelular tumor-endotelial mediada por sEV.
"Há uma opção terapêutica curativa limitada para pacientes com câncer. Compreender a base molecular do câncer de fígado fornecerá insights sobre novas estratégias eficazes para tratar o câncer de fígado. Neste estudo, identificamos um papel funcional fundamental do vWF transportado pelo sEV circulante obtido do avançado estadiamento de pacientes com câncer de fígado na indução da neoangiogênese.
"Nosso estudo não apenas descobriu o papel e a base molecular do vWF administrado pelo sEV no câncer de fígado, mas também sugeriu que o bloqueio da comunicação intercelular dentro do microambiente tumoral é uma nova abordagem terapêutica para o câncer de fígado", disse a professora Judy Yam Wai-ping, professor do Departamento de Patologia da Faculdade de Medicina Clínica da HKUMed.
Mais informações: Samuel Wan Ki Wong et al, Pequeno vWF derivado de vesículas extracelulares induz um ciclo de feedback positivo entre células tumorais e endoteliais para promover angiogênese e metástase no carcinoma hepatocelular, Advanced Science (2023). DOI: 10.1002/advs.202302677
Informações da revista: Ciência Avançada