Tsopanoglou Nikos E, Maragoudakis Michael E
Department of Pharmacology, Medical School, University of Patras, 25110 Patras, Greece.
Semin Thromb Hemost. 2004 Feb;30(1):63-9. doi: 10.1055/s-2004-822971.
Clinical, laboratory, histopathological, and pharmacological evidence support the notion that the coagulation system, which is activated in most cancer patients, plays an important role in tumor biology. Our laboratory has provided evidence that thrombin activates angiogenesis, a process which is essential in tumor growth and metastasis. This event is independent of fibrin formation. At the cellular level many actions of thrombin can contribute to activation of angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach to basement membrane proteins. (2). Thrombin greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This potentiation is accompanied by up-regulation of the expression of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt-1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3) integrin and serves as a ligand to this receptor. Furthermore, thrombin increases the secretion of VEGF and enhances the expression and protein synthesis of matrix metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic and tumor-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.
临床、实验室、组织病理学和药理学证据均支持以下观点：在大多数癌症患者体内被激活的凝血系统在肿瘤生物学中发挥着重要作用。我们实验室已提供证据表明，凝血酶可激活血管生成，这一过程在肿瘤生长和转移中至关重要。该事件与纤维蛋白形成无关。在细胞水平上，凝血酶的许多作用都可能有助于血管生成的激活：（1）凝血酶降低内皮细胞附着于基底膜蛋白的能力。（2）凝血酶极大地增强血管内皮生长因子（VEGF）诱导的内皮细胞增殖。这种增强伴随着VEGF受体（含激酶插入结构域受体[KDR]和fms样酪氨酸激酶[Flt-1]）表达的上调。（3）凝血酶增加α（v）β（3）整合素的mRNA和蛋白质水平，并作为该受体的配体。此外，凝血酶增加VEGF的分泌，并增强人前列腺癌PC-3细胞中基质金属蛋白酶-9和α（v）β（3）整合素的表达及蛋白质合成。这些结果可以解释凝血酶的血管生成和促肿瘤作用，并为开发用于治疗的凝血酶受体模拟物或拮抗剂提供依据。
