Tumor therapy with antiangiogenic beta-2-glycoprotein 1

描述(申请人提供)：在伤口愈合过程中，控制纤维蛋白凝块形成和溶解的几种负向血管生成调节剂是相同的蛋白质。这些凝血蛋白包括抗凝血酶III、凝血酶原和纤维蛋白原及其蛋白分解片段、凝血酶原片段-1和-2以及血管抑素。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准确地量化新血管的形成，我们观察到嵌入的beta2GBP1完全阻止新血管进入植入物，这表明它可以抑制肿瘤血管生成。使用B16黑色素瘤、UV2237纤维肉瘤和前列腺癌TRAMP小鼠肿瘤模型进行的治疗研究表明，重复给予该蛋白显著抑制了所有研究对象的肿瘤生长和B16黑色素瘤模型中的肺转移。体外研究表明，Beta2GBP1特异性地抑制 内皮细胞的生长、索的形成和细胞的迁移，提示抑制肿瘤生长可能是由于抑制了血管生成。另一方面，对该蛋白对体内正常血管系统的影响的研究表明，该蛋白完全抑制了生长因子诱导的血管扩张，但不能抑制化学诱导的血管扩张，这表明抑制肿瘤生长是通过血管扩张依赖的机制发生的。在这项提案中，我们将研究依赖于Beta2GBP1的抑制肿瘤细胞生长的机制及其作为一种新的癌症治疗方式的潜力。

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.