c-Met activation in medulloblastoma induces tissue factor expression and activity: effects on cell migration

Abstract

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.

Investigation of brain tissue infiltration by medulloblastoma cells in an ex vivo model

“…In contrast, when the co-culture was treated with HGF alone, no appreciable increase of tumour mass over the controls was observed using volumetric analysis despite a moderate increase in slice occupancy. This data diverged from the previously described pro-migratory function of HGF in MB 23,24,32,33 . Although we do not fully understand this discrepancy yet, it is possible that HGF stimulation causes a diffuse infiltration of single cells into the cerebellum tissue with no apparent proliferation of the primary tumour mass.…”

Marker Expression in Circulating Cancer Cells of Pancreatic Cancer Patients

“…h-TERT is expressed in the majority of malignant tumor tissues [7,8] with weak or moderate telomerase activity in some precancerous lesions [10]. In the present work, h-TERT was expressed in all 25 pancreatic cancer patients at stages I, II, or III.…”

EGF as a New Therapeutic Target for Medulloblastoma Metastasis

“…A large number of laboratories have demonstrated concentration- and concentration gradient-dependent behavior of non-cancerous cells, such as fibroblasts (33) , retinal progenitor cells (69) and keratinocytes (64) , as well as tumors found in breast (57) , colon (17) and CNS cancers (2) . Our own laboratory has illustrated that select populations of cells derived from CNS tumors can respond acutely via migration to ultra-low concentration gradients of select chemoattractants (2, 14, 33) , while others have shown greater chemotactic response with specific dosage (3, 49, 56) . Microfluidic analysis is, thus, well positioned to meaningfully aid in the development of migration-targeted therapies for MB via insight of migratory parameters relevant to metastasis, such as cell distance traveled, motility, gradient-sensitivity, ECM interaction and numerous others.…”