ROLE OF Bcl-2 AND Bcl-XL IN ANGIOGENESIS

AUTOR(ES)
FONTE

IBICT - Instituto Brasileiro de Informação em Ciência e Tecnologia

DATA DE PUBLICAÇÃO

2006

RESUMO

(...)Angiogenesis is defined as the development of new capillaries from pre-existing blood vessels. The hypothesis that tumor growth is angiogenesis dependent was proposed by Judah Folkman in 1971, and it has been confirmed by many investigators thereafter. We have shown that vascular endothelial growth factor (VEGF) induces Bcl-2 expression in endothelial cells, and that Bcl-2 upregulation in tumor-associated endothelial cells is sufficient to enhance tumor growth. Most of the work performed on the Bcl-2 protein family has been focused on regulation of cell survival. However, work on the effect of these proteins on cell differentiation has emerged recently. This thesis is focused on the study of the role of Bcl-2 and Bcl-XL on endothelial cell biology and angiogenesis. Tumors secrete a panel of angiogenic factors to recruit and sustain their own microvascular network, necessary for tumor survival, proliferation, and metastasis. In addition, several members of the Bcl-2 protein family have been shown to be upregulated in tumor microenvironments. Among these tumor-induced factors, VEGF, and B-cell CLL/lymphoma 2 (Bcl-2) are considered tumor prognostic markers, being highly expressed in several tumor types. To enhance the expression of such angiogenic and survival genes simultaneously, tumor cells activate a number of cell signaling pathways. One of these highly activated pathways involved in tumor and endothelial cell survival is the nuclear factor kappa B (NF-kB) signaling pathway. The activation of the NF-kB pathway promotes tumor cell survival and causes chemotherapy resistance via destabilization of the tumor suppressor p53 protein, which is an extremely important tumor suppressor protein. Inhibition of NF-kB was shown to sensitize tumor cells to TNF-alfa-induced apoptosis. Cells can bypass apoptosis via NF-kB-mediated upregulation of several factors, which may also indirectly affect tumor progression and angiogenesis by attracting host cells. Tumor and tumor-attracted cells were shown to express chemokines that have pleiotropic effects and regulate immunity, stem cell trafficking, and mediate organ-specific metastases and angiogenesis. Many inflammatory and angiogenic chemokines are NF-kB target genes, for example the angiogenic chemokines (chemokine CXC motif ligand 8, i.e. interleukin 8) and CXCL1 (chemokine CXC motif ligand 1, i.e. growth-related oncongene-alpha). These chemokines exert their angiogenic function via binding to specific receptors. CXCL8 binds to CXC receptor 1 (CXCR1) and CXC receptor 2 (CXCR2), while CXCL1 binds exclusively to CXCR2. Interestingly, the upregulation of CXCR2 ligands, such as CXCL8 and CXCL1, was demonstrated to contribute to the expansion of early alveolar neoplastic lesions. CXCR2 is an important CXC receptor expressed by normal endothelial cells, and it was also found on tumor-associated-endothelial cells within the tumors. Notably, recent findings demonstrate that the majority, if not all, angiogenic activity of CXC chemokines, including CXCL8, is mediated through CXCR2. In summary, tumor progression is dependent on endothelial cell survival and function, and VEGF and Bcl-2 protein family members represent key molecules in these two processes. Here we demonstrate that, VEGF and Bcl-2 protein family members play a role as initiators of an angiogenic cascade in endothelial cells, which result in activation of the NF-kB signaling pathway and expression of CXC pro-angiogenic chemokines. We firmly believe that better understanding of the mechanisms and signaling pathways mediated by these molecules may lead to the development of novel therapeutic targets for the treatment of cancer.(...)

ASSUNTO(S)

biofisica molecular angiogenesis

ACESSO AO ARTIGO

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