Tumor angiogenesis is an attractive target for cancer therapy and chemoprevention. The recent proven efficacy of various anti-angiogenic therapies in recent clinical trials underscore the potential of this approach. Components of intracellular signaling pathways that regulate endothelial cell survival may provide particularly attractive molecular targets for development of such strategies, especially those pathways that regulate endothelial cell apoptosis. During angiogenesis, in order to migrate, endothelial cells must break both cell-cell and cell-extracellular matrix attachments, a process that is inherently pro-apoptotic. Our recent work demonstrates that the ras/Erk pathway nuclear effectors, Ets1 and Ets2, play a critical role in endothelial cell survival and migration during development that is specific for this cell type. The studies proposed here will define biological and molecular mechanisms by which Ets1 and Ets2 act in normal endothelial cells, and will determine whether these genes also affect tumor endothelial cell function within the tumor microenvironment. Understanding how signaling pathways involved in complicated biological processes like angiogenesis function beyond cell membranes, and the likely critical role of the extracellular matrix in this communication, is one of the leading challenges for the microenvironment field over the next 5 years. The ras/Ets pathway may provide a paradigm for studying signaling beyond cell membrane in the tumor microenvironment. Tumor angiogenesis is an attractive target for tumor therapy. This project will potentially identify new molecular targets that will be useful for triggering cell death in tumor endothelial cells, affecting tumor growth and metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053271-21
Application #
8109226
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Ault, Grace S
Project Start
1990-12-13
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
21
Fiscal Year
2011
Total Cost
$257,961
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Trikha, Prashant; Sharma, Nidhi; Opavsky, Rene et al. (2011) E2f1-3 are critical for myeloid development. J Biol Chem 286:4783-95
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Wang, Hui; Karikomi, Matt; Naidu, Shan et al. (2010) Allele-specific tumor spectrum in pten knockin mice. Proc Natl Acad Sci U S A 107:5142-7
Acharyya, Swarnali; Sharma, Sudarshana M; Cheng, Alfred S et al. (2010) TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy. PLoS One 5:e12479
Srinivasan, Ruchika; Zabuawala, Tahera; Huang, Hong et al. (2009) Erk1 and Erk2 regulate endothelial cell proliferation and migration during mouse embryonic angiogenesis. PLoS One 4:e8283

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