Sheibani N, Frazier W A
Washington University School of Medicine, Department of Biochemistry and Molecular Biophysics, St. Louis, MO 63110, USA.
Histol Histopathol. 1999 Jan;14(1):285-94. doi: 10.14670/HH-14.285.
Thrombospondin-1 (TSP1) is a multidomain glycoprotein expressed by many cell types. It is a multifunctional protein with important roles in regulation of vascular cell functions. Mutation or loss of tumor suppressor genes results in down regulation of TSP1 expression during malignant transformation. Thus, suggesting that down regulation of TSP1 may contribute to development of the tumor angiogenic phenotype and perhaps tumor metastasis. TSP1 was demonstrated to be a natural inhibitor of angiogenesis. Peptides from procollagen-like domain and type 1 repeats of TSP1, like whole TSP1, inhibit the angiogenic response to a variety of angiogenic stimuli in vivo and endothelial cell (EC) migration in vitro by directly acting on ECs. The molecular mechanisms which mediate these inhibitory effects of TSP1 and its peptides are not understood. TSP1 expression is down regulated in the Polyoma middle T transformed mouse brain ECs (bEND.3). This may remove the TSP1 inhibitory effects allowing ECs to rapidly proliferate in culture and form hemangiomas in vivo. Re-expression of TSP1 in bEND.3 cells restores a normal phenotype and suppresses their ability to form hemangiomas. This is mediated by modulating expression of several genes in concert favoring a differentiated state of endothelium. TSP1 transfected bEND.3 cells down regulate expression of PECAM-1, a multifunctional endothelial cell adhesion molecule with essential roles in angiogenesis. A similar phenotype to that of TSP1 transfected cells was observed when endogenous PECAM-1 levels were down regulated by anti-sense transfection of bEND.3 cells. The anti-sense PECAM-1 transfected cells turn on expression of endogenous TSP1 and its angioinhibitory receptor, CD36. Expression of other genes with potential roles in regulation of EC phenotype were also affected in patterns very similar to those observed in TSP1 transfected bEND.3 cells. Therefore, it appears that a reciprocal relationship exists between TSP1 and PECAM-1 such that they are constituents of a "switch" that regulates in concert many components of the angiogenic and differentiated phenotype of ECs.
血小板反应蛋白-1（TSP1）是一种由多种细胞类型表达的多结构域糖蛋白。它是一种多功能蛋白，在调节血管细胞功能中起重要作用。肿瘤抑制基因的突变或缺失导致恶性转化过程中TSP1表达下调。因此，提示TSP1表达下调可能有助于肿瘤血管生成表型的发展，甚至可能促进肿瘤转移。TSP1被证明是一种天然的血管生成抑制剂。来自TSP1前胶原样结构域和1型重复序列的肽，与完整的TSP1一样，通过直接作用于内皮细胞（EC），在体内抑制对多种血管生成刺激的血管生成反应，并在体外抑制EC迁移。介导TSP1及其肽这些抑制作用的分子机制尚不清楚。在多瘤病毒中T转化的小鼠脑内皮细胞（bEND.3）中，TSP1表达下调。这可能消除了TSP1的抑制作用，使EC在培养中迅速增殖并在体内形成血管瘤。TSP1在bEND.3细胞中的重新表达恢复了正常表型，并抑制了它们形成血管瘤的能力。这是通过协同调节几个基因的表达来介导的，有利于内皮细胞的分化状态。TSP1转染的bEND.3细胞下调PECAM-1的表达，PECAM-1是一种多功能内皮细胞粘附分子，在血管生成中起重要作用。当通过bEND.3细胞的反义转染下调内源性PECAM-1水平时，观察到与TSP1转染细胞类似的表型。反义PECAM-1转染细胞开启内源性TSP1及其血管抑制受体CD36的表达。其他在调节EC表型中可能起作用的基因的表达也受到影响，其模式与在TSP1转染的bEND.3细胞中观察到的非常相似。因此，似乎TSP1和PECAM-1之间存在相互关系，使得它们是一个“开关”的组成部分，共同调节EC血管生成和分化表型的许多成分。
