) The major objective of this proposal is to test the hypothesis that a cryptic domain of collagen-IV plays a fundamental role in the regulation of angiogenesis and tumor growth. This proposal is based on a series on observations from experiments performed with a novel monoclonal antibody (Mab HUIV 26) directed to proteolyzed collagen-IV. Collagen-IV is a major component of the subendothelial basement membrane of blood vessels, and thus, endothelial cell invasion through this collagen-IV rich barrier likely contributes to neovascularization. Importantly, the possibility that biochemical regulatory information is hidden within the three dimensional structure of specific ECM molecules has not been explored in detail. In fact, little direct evidence is available concerning the mechanism by which ECM remodeling contributes to angiogenesis. To this end, our preliminary findings suggest that Mab HUIV26 specifically recognizes a cryptic domain in collagen- IV which is inaccessible within mature native collagen-IV but is exposed following proteolysis. Moreover, our finding suggest that this HUIV26 cryptic domain is specifically exposed within the subendothelial basement membrane of tumor associated blood vessel in vivo. Furthermore, preliminary results suggest that systemic administration of Mab HUIV26 inhibits angiogenesis and tumor growth. Based on these preliminary findings, it is possible that proteolysis of collagen-IV may represent a unique mechanism by which cryptic biochemical information is transferred to endothelial cells, thereby regulating angiogenesis and tumor growth. Thus, the identification and functional characterization of this cryptic domain, may lead to the development of novel therapeutic approaches for the treatment of pathological neovascularization and malignant tumor growth.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA091645-01
Application #
6344203
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (J1))
Project Start
2000-09-15
Project End
2005-08-31
Budget Start
2000-09-15
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$284,193
Indirect Cost
Name
New York University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Caron, Jennifer M; Ames, Jacquelyn J; Contois, Liangru et al. (2016) Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope. Am J Pathol 186:1649-61
Ames, Jacquelyn J; Contois, Liangru; Caron, Jennifer M et al. (2016) Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway. J Biol Chem 291:2731-50
Young, Kira; Tweedie, Eric; Conley, Barbara et al. (2015) BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PLoS One 10:e0122892
Contois, Liangru W; Akalu, Abebe; Caron, Jennifer M et al. (2015) Inhibition of tumor-associated ?v?3 integrin regulates the angiogenic switch by enhancing expression of IGFBP-4 leading to reduced melanoma growth and angiogenesis in vivo. Angiogenesis 18:31-46
Favreau, Amanda J; Vary, Calvin P H; Brooks, Peter C et al. (2014) Cryptic collagen IV promotes cell migration and adhesion in myeloid leukemia. Cancer Med 3:265-72
Duarte, Christine W; Murray, Kimberly; Lucas, F Lee et al. (2014) Improved survival outcomes in cancer patients with hereditary hemorrhagic telangiectasia. Cancer Epidemiol Biomarkers Prev 23:117-125
Gong, Yan; Yang, Xuehui; He, Qing et al. (2013) Sprouty4 regulates endothelial cell migration via modulating integrin *3 stability through c-Src. Angiogenesis 16:861-75
Contois, Liangru W; Nugent, Desiree P; Caron, Jennifer M et al. (2012) Insulin-like growth factor binding protein-4 differentially inhibits growth factor-induced angiogenesis. J Biol Chem 287:1779-89
Romero, Diana; O'Neill, Christine; Terzic, Aleksandra et al. (2011) Endoglin regulates cancer-stromal cell interactions in prostate tumors. Cancer Res 71:3482-93
Hamilton, Heather K; Rose, Amy E; Christos, Paul J et al. (2010) Increased shedding of HU177 correlates with worse prognosis in primary melanoma. J Transl Med 8:19

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