Several negative regulators of angiogenesis are the same proteins that control the formation and dissolution of fibrin clots during wound healing. These include coagulation proteins antithrombin III, prothrombin and fibrinogen and their proteolytic fragments, prothrombin fragments-1 and -2 and angiostatin. Beta-2-glycoprotein 1 (beta2GBP1), a 50 kDa plasma protein, regulates thrombosis by competing for the assembly of coagulation factors. Using a subcutaneous implant comprised of gelatin and agarose that accurately quantifies the formation of new blood vessels, we observed that embedded beta2GBP1 completely blocked the invasion of new blood vessels into the implant suggesting that it could inhibit tumor angiogenesis. Therapy studies using the B16 melanoma, UV2237 flbrosarcoma and TRAMP prostate carcinoma mouse tumor models showed that repeated administration of the protein significantly inhibited the growth of all the tumors studied and lung metastasis in the B16 melanoma model. In vitro studies showed that beta2GBP1 specifically inhibited endothelial cell growth, cord formation and cell migration, suggesting that inhibition of tumor growth might be due to inhibition of angiogenesis. Studies on the effects of the protein on normal vasculature in vivo, on the other hand, showed complete inhibition of growth factor-induced, but not chemically-induced blood vessel dilatation suggesting that inhibition of tumor growth occurred via an angioectasia-dependent mechanism. In this proposal, we will examine the mechanism of beta2GBP1-dependent inhibition of tumor cell growth and its potential as a new therapeutic modality for the treatment of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098527-02
Application #
6912807
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$237,825
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mirnikjoo, Banafsheh; Balasubramanian, Krishnakumar; Schroit, Alan J (2009) Mobilization of lysosomal calcium regulates the externalization of phosphatidylserine during apoptosis. J Biol Chem 284:6918-23
Sakai, Taro; Balasubramanian, Krishnakumar; Maiti, Sourindra et al. (2007) Plasmin-cleaved beta-2-glycoprotein 1 is an inhibitor of angiogenesis. Am J Pathol 171:1659-69
Hamdan, Randala; Maiti, Sourindra N; Schroit, Alan J (2007) Interaction of beta2-glycoprotein 1 with phosphatidylserine-containing membranes: ligand-dependent conformational alterations initiate bivalent binding. Biochemistry 46:10612-20
Lu, Weixin; Bucana, Corazon D; Schroit, Alan J (2007) Pathogenesis and vascular integrity of breast cancer brain metastasis. Int J Cancer 120:1023-6