Neovascularization is critical for the support of substantial tumor growth. For a wide range of tumors, a complex microvasculature accompanies the transition from hyperplasia to neoplasia, a progression from low to high-grade classification and enhanced metastatic capacity. Studies have demonstrated that a greater number of blood vessels often predict a more aggressive cancer. Thus targeting the new blood vessels of the tumor has been a promising approach for the treatment of tumors. We have recently demonstrated that Tissue Inhibitor of Metalloproteinases-3 (TIMP-3), an endogenous inhibitor of matrix metalloproteinases (MMP), is a potent inhibitor of Vascular Endothelial Growth Factor (VEGF) mediated angiogenesis. TIMP-3 can block the binding of VEGF specifically to its receptor, KDR on the surface of endothelial cells. Surprisingly, TIMP-3 mediates this angiostatic effect independent of its MMP inhibitory activity. These results led us to hypothesize that TIMP-3 is a potent endogenous angiogenesis inhibitor and plays a critical role in tumorigenesis. We propose to study the molecular modeling of TIMP-3 and KDR interactions. Based on these results, we will identify domains of TIMP-3 that have the angiostatic function but are devoid of MMP inhibitory activity. Since both TIMP-3 and VEGF bind heparan sulfate proteoglycans, we will determine the structural basis and potential role of heparin/heparan sulfate binding to the angiostatic activity of TIMP-3. We will also examine VEGF mediated angiogenesis and tumor growth in mice deficient in Timp-3. In the long term, the understanding of the molecular mechanisms of regulation of neovascularization by TIMP-3 will help in the design of therapeutic interventions to prevent unfettered growth of tumors.
Specific Aims : 1. To identify the TIMP-3 and KDR domains involved in TIMP-3/KDR interaction. 2. To determine the potential role of heparin/heparan sulfate binding on the angiostatic activity of TIMP-3. 3. To determine the VEGF mediated angiogenic response and tumor growth in TIMP-3 null mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA106415-01A1
Application #
6871665
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Macleod, Carol L
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$247,161
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Qi, Jian Hua; Anand-Apte, Bela (2015) Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism. Apoptosis 20:523-34
Qi, Jian Hua; Ebrahem, Quteba; Ali, Mariya et al. (2013) Tissue inhibitor of metalloproteinases-3 peptides inhibit angiogenesis and choroidal neovascularization in mice. PLoS One 8:e55667
Sugimoto, Masahiko; Cutler, Alecia; Shen, Bailey et al. (2013) Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage. Am J Pathol 183:987-95
Ebrahem, Quteba; Qi, Jian Hua; Sugimoto, Masahiko et al. (2011) Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. Invest Ophthalmol Vis Sci 52:6117-23
Tan, Kevin; Lessieur, Emma; Cutler, Alecia et al. (2010) Impaired function of circulating CD34(+) CD45(-) cells in patients with proliferative diabetic retinopathy. Exp Eye Res 91:229-37
Anand-Apte, Bela; Ebrahem, Quteba; Cutler, Alecia et al. (2010) Betacellulin induces increased retinal vascular permeability in mice. PLoS One 5:e13444
Ebrahem, Quteba; Chaurasia, Shyam S; Vasanji, Amit et al. (2010) Cross-talk between vascular endothelial growth factor and matrix metalloproteinases in the induction of neovascularization in vivo. Am J Pathol 176:496-503
Xie, Jing; Farage, Eric; Sugimoto, Masahiko et al. (2010) A novel transgenic zebrafish model for blood-brain and blood-retinal barrier development. BMC Dev Biol 10:76
Qi, Jian Hua; Dai, Ganying; Luthert, Philip et al. (2009) S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis. J Biol Chem 284:19927-36
Sears, Jonathan E; Hoppe, George; Ebrahem, Quteba et al. (2008) Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci U S A 105:19898-903

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