Tumor therapy with antiangiogenic beta-2-glycoprotein 1

使用抗血管生成 β-2-糖蛋白 1 进行肿瘤治疗

• 批准号: 7409122
• 负责人: ALAN Jay SCHROIT
• 金额: $ 22.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409122
• 关键词: Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiostatins; Antithrombin III; Biological Models; Blood Coagulation Factor; Blood Vessels; Coagulation Process; Dilatation - action; Endothelial Cells; Fibrin; Fibrinogen; Gelatin; Glycoproteins; Growth; Growth Factor Inhibition; Hand; Implant; In Vitro; Lung; Modality; Modeling; Molecular; Mus; Neoplasm Metastasis; Numbers; Pathological Dilatation; Plasma Proteins; Prostate carcinoma; Proteins; Prothrombin; Sepharose; Therapeutic; Thrombosis; Tumor Angiogenesis; Wound Healing; angiogenesis; cancer therapy; cell growth; cell motility; in vivo; melanoma; mouse model; neoplastic cell; novel therapeutics; prothrombin fragment 1; subcutaneous; tumor; tumor growth

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.

描述（由申请人提供）：血管生成的几种负调节因子与在伤口愈合过程中控制纤维蛋白凝块的形成和溶解的蛋白质相同。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以及血管抑制素。 Beta-2-糖蛋白 1 (beta2GBP1) 是一种 50 kDa 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量化新血管的形成，我们观察到嵌入的 beta2GBP1 完全阻止了新血管侵入植入物，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 TRAMP 前列腺癌小鼠肿瘤模型进行的治疗研究表明，重复施用该蛋白可显着抑制所有研究的肿瘤的生长以及 B16 黑色素瘤模型中的肺转移。体外研究表明 beta2GBP1 特异性抑制 内皮细胞生长、索状形成和细胞迁移，表明肿瘤生长的抑制可能是由于血管生成的抑制。另一方面，对该蛋白对体内正常脉管系统的影响的研究表明，它完全抑制生长因子诱导的血管扩张，但不抑制化学诱导的血管扩张，这表明肿瘤生长的抑制是通过血管扩张依赖性机制发生的。在本提案中，我们将研究β2GBP1依赖性抑制肿瘤细胞生长的机制及其作为治疗癌症的新治疗方式的潜力。