The proliferation and invasive nature of a growing tumor, and ultimately the pathologic consequence, is largely governed by its ability to undergo an """"""""angiogenic switch"""""""". With this change in phenotype, the tumors growth properties are critically aided by its acquired ability to stimulate the invasion and new growth of a capillary blood supply. Vascular Endothelial Growth Factor is a cytokine essential for vascular development and angiogenesis (13, 27). It is specific for vascular endothelium, where it is a potent mitogen, increases endothelial cell permeability, stimulates endothelial cell migration, induces differentiation, and acts as an endothelial cell survival factor (25, 126). These actions all ultimately regulate the angiogenic response. VEGF is now believed to be a critical mediator of tumor angiogenesis and this factor is markedly upregulated by cellular transformation and by the hypoxic conditions found in growing neoplasms. Dysregulation of VEGF production is now implicated as a causative agent in the hemangiomas and renal cell carcinomas of patients who have von Hippel-Lindau disease. The signal transduction mechanisms responsible for the angiogenic response remain largely unknown. This study is being undertaken to investigate the role of Ras and Ras-related signal transduction in mediating several of the known actions of VEGF related to angiogenesis. These experiments will use inducible, ectopic expression of mutant signaling molecules to genetically manipulate signal transduction pathways in primary endothelial cells. Signal transduction pathways that appear to be critical for the angiogenic responses to VEGF in vitro, will also be tested in an in vivo model of tumor angiogenesis employing xenografts of a VEGF-dependent renal cell carcinoma. This will provide a oasis for understanding angiogenesis at the molecular level and ultimately will allow for designing new approaches to therapeutically target tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA081419-02
Application #
6150389
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mohla, Suresh
Project Start
1999-04-01
Project End
2003-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$179,227
Indirect Cost
Name
Albany Medical College
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Mathew, Shomita S; Nieves, Bethsaida; Sequeira, Sharon et al. (2014) Integrins promote cytokinesis through the RSK signaling axis. J Cell Sci 127:534-45
Colello, Diane; Mathew, Shomita; Ward, Rachel et al. (2012) Integrins regulate microtubule nucleating activity of centrosome through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling. J Biol Chem 287:2520-30
Bryant, Patrick W; Zheng, Qingxia; Pumiglia, Kevin M (2012) Focal adhesion kinase is a phospho-regulated repressor of Rac and proliferation in human endothelial cells. Biol Open 1:723-30
Rajashekhar, Gangaraju; Kamocka, Malgorzata; Marin, Abby et al. (2011) Pro-inflammatory angiogenesis is mediated by p38 MAP kinase. J Cell Physiol 226:800-8
Adam, Alejandro P; Sharenko, Amy L; Pumiglia, Kevin et al. (2010) Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to decrease barrier function of endothelial monolayers. J Biol Chem 285:7045-55
Bajaj, Anshika; Zheng, Qingxia; Adam, Alejandro et al. (2010) Activation of endothelial ras signaling bypasses senescence and causes abnormal vascular morphogenesis. Cancer Res 70:3803-12
Lamar, John M; Pumiglia, Kevin M; DiPersio, C Michael (2008) An immortalization-dependent switch in integrin function up-regulates MMP-9 to enhance tumor cell invasion. Cancer Res 68:7371-9
Neskey, David M; Ambesi, Anthony; Pumiglia, Kevin M et al. (2008) Endostatin and anastellin inhibit distinct aspects of the angiogenic process. J Exp Clin Cancer Res 27:61
Choma, David P; Milano, Vincenzo; Pumiglia, Kevin M et al. (2007) Integrin alpha3beta1-dependent activation of FAK/Src regulates Rac1-mediated keratinocyte polarization on laminin-5. J Invest Dermatol 127:31-40
Bryant, Patrick; Zheng, Qingxia; Pumiglia, Kevin (2006) Focal adhesion kinase controls cellular levels of p27/Kip1 and p21/Cip1 through Skp2-dependent and -independent mechanisms. Mol Cell Biol 26:4201-13

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