Bagavandoss P, Kaytes P, Vogeli G, Wells P A, Wilks J W
Upjohn Laboratories, Kalamazoo, MI 49001.
Biochem Biophys Res Commun. 1993 Apr 30;192(2):325-32. doi: 10.1006/bbrc.1993.1418.
The angiogenic and malignant phenotypes of hamster tumor cells are inversely correlated with the expression of an amino terminally truncated thrombospondin (TSP) subunit. In the present study, we have constructed a truncated TSP subunit from a human fibroblast cDNA library (rt-TSP1) and expressed it in Chinese hamster ovary (CHO) cells. Increased concentrations of plasminogen activator inhibitor-1 (PAI-1) were detected in endothelial cell conditioned medium following treatment with rt-TSP1. This rt-TSP1-induced increase in PAI-1 was neutralized by monoclonal antibodies to both TSP and TGF beta. rt-TSP1 also inhibits the proliferation of endothelial cells and this response is also neutralized by TSP and TGF beta antibodies. Serine and cysteine proteases inhibitors were used to determine if rt-TSP1 activated the latent TGF beta. However, these protease inhibitors did not neutralize the effect of rt-TSP1. The data indicate that the anti-angiogenic properties of TSP may be due to inhibition of the pericellular proteolysis required for endothelial cell migration and endothelial cell proliferation.
仓鼠肿瘤细胞的血管生成和恶性表型与氨基末端截短的血小板反应蛋白（TSP）亚基的表达呈负相关。在本研究中，我们从人成纤维细胞cDNA文库构建了一个截短的TSP亚基（rt-TSP1），并在中国仓鼠卵巢（CHO）细胞中进行表达。用rt-TSP1处理后，在内皮细胞条件培养基中检测到纤溶酶原激活物抑制剂-1（PAI-1）浓度增加。这种rt-TSP1诱导的PAI-1增加被针对TSP和TGFβ的单克隆抗体中和。rt-TSP1还抑制内皮细胞的增殖，并且这种反应也被TSP和TGFβ抗体中和。使用丝氨酸和半胱氨酸蛋白酶抑制剂来确定rt-TSP1是否激活潜伏的TGFβ。然而，这些蛋白酶抑制剂并未中和rt-TSP1的作用。数据表明，TSP的抗血管生成特性可能是由于抑制了内皮细胞迁移和内皮细胞增殖所需的细胞周蛋白水解作用。
