Tumor therapy with antiangiogenic beta-2-glycoprotein 1

描述（由申请人提供）：几种血管生成的负调节因子是在伤口愈合过程中控制纤维蛋白凝块形成和溶解的相同蛋白质。这些包括凝血蛋白抗凝血酶III，凝血酶原和纤维蛋白原及其蛋白水解片段，凝血酶原片段-1和-2和血管抑制素。β -2糖蛋白1 （beta2GBP1）是一种50 kDa的血浆蛋白，通过竞争凝血因子的组装来调节血栓形成。使用由明胶和琼脂糖组成的皮下植入物可以准确地量化新血管的形成，我们观察到嵌入的beta2GBP1完全阻断了新血管侵入植入物，这表明它可以抑制肿瘤血管生成。B16黑色素瘤、UV2237纤维肉瘤和TRAMP前列腺癌小鼠肿瘤模型的治疗研究表明，反复给药该蛋白可显著抑制B16黑色素瘤模型中所有肿瘤的生长和肺转移。体外研究表明，β 2gbp1特异性抑制

DESCRIPTION (provided by applicant): 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.