Impacto da matriz extracelular derivada de melanoma sobre o perfil angiogênico de células endoteliais: envolvimento de vias de sinalização dependentes de integrina

• Autor(a) principal: Costa, Renata Machado Brandão
• Data de Publicação: 2014
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/16296
• topic: Melanoma; Integrins; Angiogenesis; Disintegrins; Melanoma; Integrinas Metabolismo; Neovascularização; Melanoma; Integrinas; Angiogênese; Desintegrinas; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA::FARMACOLOGIA BIOQUIMICA E MOLECULAR

Tumor progression creates a microenvironment that influences plasticity, migration and invasion of neighboring cells and triggers the formation of new blood vessels from preexisting blood vessels, a process known as angiogenesis. This process depends on the production of growth factors by tumor cells that stimulate new blood vessel growth and survival. But, adhesion to the extracellular matrix (ECM) is also important to regulate survival, proliferation and motility of endothelial cells during angiogenesis. Integrins are the major protein adhesion molecules responsible for cell-matrix interactions and transduction of signals that regulate cell shape, survival and proliferation. Integrins can also crosstalk with tyrosine kinase receptors, like VEGFR2, activating this receptor independent from the intrinsic kinase activity. Thus, it is possible to propagate downstream signals to ensure cell growth, survival and differentiation in normal and pathological angiogenesis. In our study, we investigated the effects of disintegrins, wich are selective ligands for integrins, changing the functions of the integrins. Because of this, these molecules have become important for cancer therapy development. Here, we evaluated the intracellular signaling pathways involved in interactions between tumor-derived extracellular matrix and endothelial cells and how these interactions may impact events associated with tumor angiogenesis. We showed that tumor-derived extracellular matrix, obtained from the human melanoma cell line (MV3), presents structural differences, compared with normal ECM, obtained from the human melanocyte cell line (NGM). We observed that, differently from NGM ECM, MV3 ECM increase F-actin polymerization on HMEC1, corroborating with the increase in phosphorylation of AKT and FAK. We also showed an increase in phosphorilated VEGFR2, and an increase FAK association with c-Src, on HMEC1 cultured 24 hours on MV3 ECM. Finally, we saw that desintegrins reduced F-actin polymerization and distribution in HMEC1 cultured on MV3 ECM. And yet, these disintegrins were able to inhibit the migration of the endothelial cells plated on tumoral ECM. Taken together, these data suggest that tumor matrix change endothelial cell behavior, activating integrin-depended signaling pathways which are related to important events on angiogenic process. These changes probably are potentiated by VEGFR2 activation.