Fibronectin-binding integrins in angiogenesis

University Of California, San Diego, La Jolla CA

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Abstract

Angiogenesis, the growth of new blood vessels, promotes tumor growth and metastasis. During the previous grant cycle, we found that the fibronectin receptor integrin [unreadable]4[unreadable]1 promotes tumor angiogenesis by distinct endothelial cell- and myeloid cell-mediated mechanisms. Our studies showed that endothelial cell integrin [unreadable]4[unreadable]1 promotes tumor angiogenesis and growth. We observed that 1) integrin [unreadable]4[unreadable]1 is expressed on growth factor- and tumor-induced but not normal blood vessels;2) integrin [unreadable]4 antagonists block endothelial cell migration and survival and suppress developmental and tumor angiogenesis, as well as tumor growth and metastasis;3) endothelial cell specific deletion of [unreadable]4 (Tie2Cre+Itga4 loxp/loxp) inhibited angiogenesis, as did an integrin [unreadable]4 cytoplasmic tail knockin mutation (Itga4Y991A/Y991A) that prevents integrin [unreadable]4[unreadable]1 activation, and 4) VEGF-A stimulates endothelial cell integrin [unreadable]4 activation by inducing the binding of paxillin to the [unreadable]4 cytoplasmic tail. Our studies indicate that endothelial cell integrin [unreadable]4[unreadable]1 may serve as a tumor biomarker and as a target for novel anti-tumor therapies. Our studies showed that integrin [unreadable]4[unreadable]1 promotes endothelial cell invasion in tumors, with subsequent tumor angiogenesis, growth and metastasis. We observed that 1) chemoattractants released from tumor cells, such as SDF-1[unreadable] or VEGF stimulate PI-3-kinase alpha- and paxillin-dependent [unreadable]4[unreadable]1 mediated migration of endothelial cells and that 2) antibody antagonists of [unreadable]4[unreadable]1 blocked tumor angiogenesis and progression, and 3) mutations that impaired expression or activation of [unreadable]4[unreadable]1 (Tie2Cre+Itga4 loxp/loxp and Itga4Y991A/Y991A) blocked tumor angiogenesis, growth and metastasis. Our studies indicate that integrin [unreadable]4[unreadable]1 activation in endothelial cells depends on PI3kinase alpha and antagonism of integrin )4(R)1 activation or function represents a new approach to control tumor progression. We therefore propose to test the hypothesis that integrin [unreadable]4[unreadable]1 activation by cytokine-induced signaling pathways is required for endothelial cell-mediated tumor angiogenesis and growth. The specific aims for this proposal are: 1) To identify receptor-mediated signaling pathways by which tumor derived factors activate endothelial cell integrin )4(R)1 to promote adhesion and invasion, and 2) To evaluate endothelial cell integrin )4(R)1 to serve as a biomarker for tumor diagnosis and as a target for anti-tumor therapy.