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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA083133-10
Application #
7729637
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1999-09-01
Project End
2011-06-30
Budget Start
2009-07-16
Budget End
2010-06-30
Support Year
10
Fiscal Year
2009
Total Cost
$305,550
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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