219 MET ECD shedding and use of targeted therapies Although never formally proven, it is plausible that an increase of MET ectodomain shedding in OSCC results from GPCR mediated EGFR transactivation. Increased mRNA and protein levels of the metalloproteases ADAM10 and ADAM17, responsible for MET ectodomain shedding, increase invasive behavior of OSCC and are accordingly associated with advanced tumor stages, regional lymph node metastasis, and reduced survival (51, 52). Overall, it appears that GPCR transactivation of EGFR (50) and overexpression of ADAM10/17, as observed in OSCC (51, 52), result in the increased rate of MET ectodomain shedding. In combination with MET overexpression, as observed in the majority of OSCC cases (53), this results in the increased concentration of MET-EC- fragments on the tumor cell membrane thus enhancing their stabilization (e.g. by dimerization or oligomerization) and constitutive activation, as also observed by Merlin et al. in NIH-3T3 cells (45) (Figure 2B). Although MET ectodomain shedding occurs in OSCC and differences between C- and N-terminal MET immunoreactivity are associated with poor survival (42, 47), it has never been formally proven that a fully functional phosphorylated MET-EC- exists in OSCC. Nevertheless, we hypothesize on the potential value of shedding in the stratification of patients with OSCC eligible for treatment with MET-targeted therapies. MET-EC- as biomarker in OSCC Accurate C- and N-terminal MET IHC analysis has allowed us to stratify resection specimens from patients diagnosed with primary and treatment-naive OSCC into three categories: MET negative (no MET immunoreactivity), decoy MET (more positivity for the N-terminal moAb), and transmembranous C-terminal MET (equal positivity for both moAb’s (complete MET) or more positivity for the C-terminal moAb (complete MET and/or MET-EC-)) (42, 46). As OSCC patients falling in the third category developed cancers that are positive for the protein’s catalytic domain, they are likely to be eligible for MET-targeted therapies. Accordingly, an association between C-terminal MET immunoreactivity and survival was established (42). Since a subpopulation of the C-terminal MET-positive patients show no immunoreactivity for the N-terminus, and therefore are presumed to show a suboptimal response to MET moAbs, an association between the difference between C- and N-terminal MET (MET-EC-) and poor survival was also established (42, 47), a result that is concurrent with the tumor-promoting potential of MET-EC- (45). Hence, both C-terminal MET 7
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