In this renewal application we propose to continue our studies on the structure, enzyme activity, and biological role of both avian and human matrix metalloproteases (MMPs). A number of new approaches and model systems that were developed during the present period of support, along with the discovery of a new MMP, will be followed up and utilized to gain insight into specific aspects of normal and malignant cell behavior that are influenced directly by the MMPs. The study will be comprehensive in that an avian MMP will be cloned and identified, a human MMP will be characterized in vitro and in vivo, and a model system for angiogenesis will be examined in terms of the involvement of both avian and human MMPs. A new avian MMP, a 75-80 kDa gelatinase, has been detected, isolated, and partially characterized. We propose to clone and identify this enzyme which may be a new member of the MMP family. Its natural activator, inhibitor, and substrates will be sought, along with its embryonic tissue source and developmental pattern of expression. We will examine the activation of human proMMP-9 by a converging protease cascade involving serine proteases (uPA and plasmin) and a metalloprotease (MMP-3). The activation of proMMP-9 will be studied in a number of complex cell co-culture systems and an in vivo tumor invasion system. Advantage will be taken of a newly- discovered blocking function of some of our anti-MMP-9 monoclonal antibodies to delineate the contribution of MMP-9 activation. An in vivo angiogenesis model system has been established that can be directly observed, quantitated, and subjected to molecular intervention. The host of the model system is a chick embryo and thus our unique species-specific MMP reagents will be utilized to examine the catalytic role of chicken and human MMPs in the vascular remodeling that occurs during in vivo angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055852-09
Application #
6375923
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Woodhouse, Elizabeth
Project Start
1992-03-15
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
9
Fiscal Year
2001
Total Cost
$283,132
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Deryugina, Elena I; Quigley, James P (2015) Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature. Matrix Biol 44-46:94-112
Deryugina, Elena I; Quigley, James P (2010) Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta 1803:103-20
Ardi, Veronica C; Van den Steen, Philippe E; Opdenakker, Ghislain et al. (2009) Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathway. J Biol Chem 284:25854-66
Conn, Erin M; Botkjaer, Kenneth A; Kupriyanova, Tatyana A et al. (2009) Comparative analysis of metastasis variants derived from human prostate carcinoma cells: roles in intravasation of VEGF-mediated angiogenesis and uPA-mediated invasion. Am J Pathol 175:1638-52
Blouse, Grant E; Botkjaer, Kenneth A; Deryugina, Elena et al. (2009) A novel mode of intervention with serine protease activity: targeting zymogen activation. J Biol Chem 284:4647-57
Wortmann, Andreas; He, Yaowu; Deryugina, Elena I et al. (2009) The cell surface glycoprotein CDCP1 in cancer--insights, opportunities, and challenges. IUBMB Life 61:723-30
Conn, Erin M; Madsen, Mark A; Cravatt, Benjamin F et al. (2008) Cell surface proteomics identifies molecules functionally linked to tumor cell intravasation. J Biol Chem 283:26518-27
Deryugina, Elena I; Quigley, James P (2008) Chick embryo chorioallantoic membrane model systems to study and visualize human tumor cell metastasis. Histochem Cell Biol 130:1119-30
Deryugina, Elena I; Quigley, James P (2008) Chapter 2. Chick embryo chorioallantoic membrane models to quantify angiogenesis induced by inflammatory and tumor cells or purified effector molecules. Methods Enzymol 444:21-41
Ardi, Veronica C; Kupriyanova, Tatyana A; Deryugina, Elena I et al. (2007) Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 104:20262-7

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