Carcinogenesis Advance Access originally published online on April 9, 2009
Carcinogenesis 2009 30(7):1089-1096; doi:10.1093/carcin/bgp085
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c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration
1 Laboratoire de médecine moléculaire, Université du Québec à Montréal, C.P. 8888, Succursale Center-ville, Montréal, Québec, Canada H3C 3P8
2 Service d'Hématologie-Oncologie
3 Département de Pathologie, Hôpital Sainte-Justine, 3175 Chemin Côte-Sainte-Catherine, Montréal, Québec, Canada H3T 1C5
* To whom correspondence should be addressed. Tel: +1 514 987 3000 ext. 8551; Fax: +1 514 987 0246; Email: oncomol{at}nobel.si.uqam.ca
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.
Abbreviations: CNS, central nervous system; Csk, C-terminal Src kinase; FVII, factor VII; HGF, hepatocyte growth factor; MB, medulloblastoma; PBS, phosphate-buffered saline; RTK, receptor tyrosine kinase; RT–PCR, reverse transcription–polymerase chain reaction; siRNA, small interfering ribonucleic acid; TF, tissue factor; TFPI, tissue factor pathway inhibitor
Received November 17, 2008; revised March 25, 2009; accepted April 4, 2009.
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