c-MET activated pathways and their implication in TGCTs oncogenesis

HGF/C-MET system has a very intricate signalling whose importance is well known during embryogenesis. c-MET de-regulation is widely described in several human cancers, and for this purpose, it is used as a target in several personalized therapies (www.vai.org/met). Though, few data are present in literature about this system in TGCTs. c-MET is encoded on chromosome 7, region 7q31. A duplication of this chromosome was described in TGCT patients. Noteworthy, high levels of HGF in serum plasma of patients affected by TGCT were found. TGCTs are a group of pathologies that arise from altered testicular niche during embryogenesis. This alteration is responsible for a block of gonocyte differentiation, which can give rise to all type II TGCTs. TGCTs are mostly curable, but there is still a little percentage of patients who develop drug resistance, radio-resistance, or long-term toxicity due to the used chemo- and radio-therapy. For these reasons, as well as for the young age of the patients and the increasing incidence in recent years, it is a paramount to have a better understanding on the onset and progression of TGCTs. In a previous work we demonstrated that c-MET is expressed by several cell lines derived from type II TGCTs and that HGF administration determines strong biological responses, especially in non-seminoma cell lines. In line with these results, we also observed that c-MET was present in human biopsies derived from patients affected by all type II TGCTs (102). In order to better characterize onset and progression of TGCTs, we decided to investigate: 1) The specific role of the c-MET receptor in chemotaxis and collective migration (continuing the previous work). 2) The signalling pathways triggered by HGF and mediated by c-MET activation, by identifying the main adaptor proteins related to it in NT2D1 cells and their role. 3) The synergic relationship among different activated adaptors in NT2D1 cells. 4) The differential HGF expression in biopsies derived from patients affected by type II TGCTs with specific concern on SE and EC.