Bevacizumab: more than an anti-angiogenic drug

• Autor(a) principal: Almeida, Cátia Alexandra Rebelo de
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/65518
• topic: tumor-induced angiogenesis; Bevacizumab; zebrafish larvae xenografts; metastatic potential; innate immune system; M2-like macrophages; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Cancer cells interact with a variety of non-tumor cell types, participating cooperatively in cellular events during cancer development, as tumor-induced angiogenesis. Although Judah Folkman thought about blood vessels as sources of oxygen and nutrients essential for tumor growth, evidences suggest that tumor neovasculatures are structurally and functionally abnormal, leading to a microenvironment prompt to induce metastasis and tumor resistance to therapies. VEGF-A is the most potent pro-angiogenic factor and is upregulated in most tumors. To overcome it, therapies were developed to target VEGF family through the neutralization of VEGF-A ligand, as Bevacizumab, or the respective receptors. The main goal of this research project was to challenge zebrafish xenograft model to reveal differential tumor responses to Bevacizumab, so that it can, eventually, be used in the future to select the eligible patients for this therapy. For that, zebrafish xenografts were generated using cancer cell lines and several hallmarks of cancer were analyzed by confocal microscopy. Our data show that zebrafish xenografts are able to unveil different responses to Bevacizumab, allowing to infer localized tumor responses, but also the impact of the anti-angiogenic compound on metastatic potential, tumor- induced angiogenesis and modulation of immunity. In more detail: Bevacizumab can induce tumor size reduction; specifically interfere with different steps of invasion-metastatic cascade event; impair tumor-induced angiogenesis in sensitive and VEGF-A-dependent tumor-related blood vessels; normalize the remaining blood vessels and selectively act on innate immune cells. In particular, experiments in a triple negative breast cancer model revealed that Bevacizumab reduces tumor size by impairing the M2-like macrophage population, which seems to be crucial for breast tumor cells survival. Altogether, our data validate zebrafish larvae xenograft model as an in vivo platform for Bevacizumab screening. Moreover, highlight the importance of explore the impact of therapies on the immune landscape and how it can influence tumor responses.