Angiogenesis, the growth of new blood vessels, promotes tumor growth and metastasis. During the previous grant cycle, we found that the fibronectin receptor integrin ?4?1 promotes tumor angiogenesis by distinct endothelial cell- and myeloid cell-mediated mechanisms. Our studies showed that endothelial cell integrin ?4?1 promotes tumor angiogenesis and growth. We observed that 1) integrin ?4?1 is expressed on growth factor- and tumor-induced but not normal blood vessels;2) integrin ?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 ?4 (Tie2Cre+Itga4 loxp/loxp) inhibited angiogenesis, as did an integrin ?4 cytoplasmic tail knockin mutation (Itga4Y991A/Y991A) that prevents integrin ?4?1 activation, and 4) VEGF-A stimulates endothelial cell integrin ?4 activation by inducing the binding of paxillin to the ?4 cytoplasmic tail. Our studies indicate that endothelial cell integrin ?4?1 may serve as a tumor biomarker and as a target for novel anti-tumor therapies. Our studies showed that integrin ?4?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? or VEGF stimulate PI-3-kinase alpha- and paxillin-dependent ?4?1 mediated migration of endothelial cells and that 2) antibody antagonists of ?4?1 blocked tumor angiogenesis and progression, and 3) mutations that impaired expression or activation of ?4?1 (Tie2Cre+Itga4 loxp/loxp and Itga4Y991A/Y991A) blocked tumor angiogenesis, growth and metastasis. Our studies indicate that integrin ?4?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 ?4?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.
Tumor growth and metastasis both depend on angiogenesis, the development of new blood vessels. Our studies show that a key cell adhesion protein, integrin ?4?1, promotes endothelial cell migration and survival during angiogenesis and also promotes myeloid cell invasion of growing tumors. Our proposed study of the mechanisms by which integrin ?4?1 in endothelial and myeloid cells promotes angiogenesis and tumor growth may lead to the development of new therapeutics based on inhibiting the function or activation of integrin ?4?1.
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