Provençal Mathieu, Labbé David, Veitch Ryan, Boivin Dominique, Rivard Georges-Etienne, Sartelet Hervé, Robitaille Yves, Gingras Denis, Béliveau Richard
Laboratoire de médecine moléculaire, Université du Québec à Montréal, C.P. 8888, Succursale Center-ville, Montréal, Québec, Canada.
Carcinogenesis. 2009 Jul;30(7):1089-96. doi: 10.1093/carcin/bgp085. Epub 2009 Apr 9.
Met, the receptor for hepatocyte growth factor (HGF), is a receptor tyrosine kinase that has recently emerged as an important contributor to human neoplasia. In physiological and pathological conditions, Met triggers various cellular functions related to cell proliferation, cell migration and the inhibition of apoptosis, and also regulates a genetic program leading to coagulation. Since medulloblastomas (MBs) express high levels of tissue factor (TF), the main initiator of blood coagulation, we therefore examined the link between Met and TF expression in these pediatric tumors. We observed that stimulation of the MB cell line DAOY with HGF led to a marked increase of TF expression and procoagulant activity, in agreement with analysis of clinical MB tumor specimens, in which tumors expressing high levels of Met also showed high levels of TF. The HGF-dependent increase in TF expression and activity required Src family kinases and led to the translocation of TF to actin-rich structures at the cell periphery, suggesting a role of the protein in cell migration. Accordingly, addition of physiological concentrations of the TF activator factor VIIa (FVII) to HGF-stimulated DAOY cells promoted a marked increase in the migratory potential of these cells. Overall, these results suggest that HGF-induced activation of the Met receptor results in TF expression by MB cells and that this event probably contribute to tumor proliferation by enabling the formation of a provisional fibrin matrix. In addition, TF-mediated non-hemostatic functions, such as migration toward FVIIa, may also play a central role in MB aggressiveness.
肝细胞生长因子（HGF）的受体Met是一种受体酪氨酸激酶，最近已成为人类肿瘤形成的重要促成因素。在生理和病理条件下，Met触发与细胞增殖、细胞迁移和细胞凋亡抑制相关的各种细胞功能，还调节导致凝血的遗传程序。由于髓母细胞瘤（MBs）表达高水平的组织因子（TF），即血液凝固的主要启动因子，因此我们研究了这些儿科肿瘤中Met与TF表达之间的联系。我们观察到，用HGF刺激MB细胞系DAOY会导致TF表达和促凝血活性显著增加，这与对临床MB肿瘤标本的分析一致，在这些标本中，表达高水平Met的肿瘤也显示出高水平的TF。HGF依赖的TF表达和活性增加需要Src家族激酶，并导致TF转位至细胞周边富含肌动蛋白的结构，提示该蛋白在细胞迁移中起作用。因此，向HGF刺激的DAOY细胞中添加生理浓度的TF激活因子VIIa（FVII）可显著促进这些细胞迁移潜能的增加。总体而言，这些结果表明，HGF诱导的Met受体激活导致MB细胞表达TF，这一事件可能通过促成临时纤维蛋白基质的形成而有助于肿瘤增殖。此外，TF介导的非止血功能，如向FVIIa迁移，也可能在MB的侵袭性中起核心作用。
