Abstract

Angiogenesis, the sprouting of new capillaries from existing vessels, is an important process that governs embryonic development, reproduction, wound healing, and a spectrum of diseases including cancer. Recent studies have shown that angiogenesis is essential for the growth of solid tumors beyond a certain size, and intervention with tumor angiogenesis can dramatically restrict tumor development. Thus, understanding the control of angiogenesis has emerged as a challenge of fundamental biological significance, and may lead to therapeutic possibilities for the treatment of cancer. Through the characterization of growth factor induced genes, a new angiogenic inducer has been recently discovered. Cyr61, encoded by a growth factor inducible, immediate early gene, promotes endothelial cell adhesion, enhances growth factor induced DNA synthesis in endothelial cells, stimulates directed capillary endothelial cell migration in vitro, and induces neovascularization in vivo. Cyr61 is a novel ligand of the integrin alphavbeta3, known to be important for angiogenesis. Furthermore, expression of cyr61 in a tumor cell line that does not normally express it enhances the size and vascularization of tumors that develop from these cells. Cyr61 is a member of a conserved protein family, suggesting that other members of this family may also regulate antiogenesis. Together, these findings suggest that Cyr61 and related proteins are novel angiogenic regulators whose activities and functions merit further investigation. The activities and functions of Cyr61 and related proteins are examined in this proposal through several approaches. First, the angiogenic activities of these proteins will be determined and the role of integrin alphavbeta3 in their actions will be assessed. Second, the structure and function relationships of Cyr61 will be analyzed. Third, the role of Cyr61 in tumor growth and metastasis will be evaluated, and intervention of Cyr61 activities will be explored as a means of restricting tumor growth.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080080-05
Application #
6626628
Study Section
Pathology A Study Section (PTHA)
Program Officer
Ault, Grace S
Project Start
1999-01-01
Project End
2004-12-31
Budget Start
2003-01-01
Budget End
2004-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$307,264
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Lin, Cristiane G; Chen, Chih-Chiun; Leu, Shr-Jeng et al. (2005) Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing. J Biol Chem 280:8229-37
Leu, Shr-Jeng; Chen, Ningyu; Chen, Chih-Chiun et al. (2004) Targeted mutagenesis of the angiogenic protein CCN1 (CYR61). Selective inactivation of integrin alpha6beta1-heparan sulfate proteoglycan coreceptor-mediated cellular functions. J Biol Chem 279:44177-87
Chen, Ningyu; Leu, Shr-Jeng; Todorovic, Viktor et al. (2004) Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. J Biol Chem 279:44166-76
Lin, Cristiane G; Leu, Shr-Jeng; Chen, Ningyu et al. (2003) CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem 278:24200-8
Schober, Joseph M; Lau, Lester F; Ugarova, Tatiana P et al. (2003) Identification of a novel integrin alphaMbeta2 binding site in CCN1 (CYR61), a matricellular protein expressed in healing wounds and atherosclerotic lesions. J Biol Chem 278:25808-15
Leu, Shr-Jeng; Liu, Ying; Chen, Ningyu et al. (2003) Identification of a novel integrin alpha 6 beta 1 binding site in the angiogenic inducer CCN1 (CYR61). J Biol Chem 278:33801-8
Schober, Joseph M; Chen, Ningyu; Grzeszkiewicz, Tatiana M et al. (2002) Identification of integrin alpha(M)beta(2) as an adhesion receptor on peripheral blood monocytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2): immediate-early gene products expressed in atherosclerotic lesions. Blood 99:4457-65
Grzeszkiewicz, Tatiana M; Lindner, Volkhard; Chen, Ningyu et al. (2002) The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology 143:1441-50
Leu, Shr-Jeng; Lam, Stephen C-T; Lau, Lester F (2002) Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cells. J Biol Chem 277:46248-55
Grzeszkiewicz, T M; Kirschling, D J; Chen, N et al. (2001) CYR61 stimulates human skin fibroblast migration through Integrin alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, independent of its carboxyl-terminal domain. J Biol Chem 276:21943-50

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