Angiogenesis, the growth of new blood vessels, promotes cancer, neovascular eye disease, psoriasis, and rheumatoid arthritis. Adhesion to provisional ECM proteins such as fibronectin is required for endothelial cell survival, proliferation and motility during new blood vessel growth. Our studies demonstrate that two fibronectin receptors, integrins alpha5beta1alpha5beta1 and alpha4beta1, play critical, but distinct, roles in the regulation of angiogenesis. Antagonists of both integrins potently inhibit angiogenesis and tumor growth. However, these integrins differ in their expression patterns and possible modes of action. Integrin alpha5beta1 is expressed on proliferating vascular endothelium in response to activation of the transcription factor Hox D3, which is induced by pro-angiogenic growth factors. Integrin alpha5beta1 then promotes the migration and survival of proliferating endothelial cells in vitro and in vivo. Our studies demonstrate that integrin a5b1 antagonists activate PKA, which then induces endothelial cell apoptosis and inhibition of angiogenesis in vivo. In contrast, integrin alpha4beta1 is poorly expressed by either quiescent or proliferating endothelium in tissues, but is expressed by circulating endothelial progenitor cells. In fact, antagonists of this integrin inhibit the participation of endothelial progenitor cells in growth factor-induced angiogenesis. The overall goal of this proposal is to explore the different mechanisms by which these two distinct fibronectin receptors regulate angiogenesis. We will test the hypotheses that integrin alpha5beta1 regulates vascular cell adhesion, migration, survival and vessel morphogenesis in vitro and in vivo in a PKA-dependent manner. We will also test the hypothesis that integrin alpha4beta1 regulates adhesion, migration, and survival of endothelial progenitor cells and other vascular cells during angiogenesis. Together these proposed studies will delineate the mechanisms by which fibronectin-binding integrins regulate angiogenesis and may lead to new therapies for cancer and other neovascular diseases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Snyderwine, Elizabeth G
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Foubert, Philippe; Kaneda, Megan M; Varner, Judith A (2017) PI3K? Activates Integrin ?4 and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression. Cancer Immunol Res 5:957-968
Kaneda, Megan M; Cappello, Paola; Nguyen, Abraham V et al. (2016) Macrophage PI3K? Drives Pancreatic Ductal Adenocarcinoma Progression. Cancer Discov 6:870-85
Gunderson, Andrew J; Kaneda, Megan M; Tsujikawa, Takahiro et al. (2016) Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov 6:270-85
Garmy-Susini, Barbara; Avraamides, Christie J; Desgrosellier, Jay S et al. (2013) PI3K? activates integrin ?4?1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci U S A 110:9042-7
Schmid, Michael C; Franco, Irene; Kang, Sang Won et al. (2013) PI3-kinase ? promotes Rap1a-mediated activation of myeloid cell integrin ?4?1, leading to tumor inflammation and growth. PLoS One 8:e60226
Foubert, Philippe; Varner, Judith A (2012) Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol Biol 757:471-86
Schmid, Michael C; Avraamides, Christie J; Foubert, Philippe et al. (2011) Combined blockade of integrin-?4?1 plus cytokines SDF-1? or IL-1? potently inhibits tumor inflammation and growth. Cancer Res 71:6965-75
Schmid, Michael C; Avraamides, Christie J; Dippold, Holly C et al. (2011) Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3k?, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19:715-27
Garmy-Susini, Barbara; Avraamides, Christie J; Schmid, Michael C et al. (2010) Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 70:3042-51
Jin, Hui; Garmy-Susini, Barbara; Avraamides, Christie J et al. (2010) A PKA-Csk-pp60Src signaling pathway regulates the switch between endothelial cell invasion and cell-cell adhesion during vascular sprouting. Blood 116:5773-83

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