237 General discussion, conclusion, and future perspective the uniform positive C-terminal MET staining pattern and/or shedding can exist alongside areas that contain decoy MET. Reexamination of the scores obtained for chapter 5, revealed that this is indeed the case for 11 out of 38 decoy MET cancers (29.0%). Performing receiver operating characteristic curve analysis, indicated that ≥ 10% of the D1C2 uniform staining pattern remained the optimal threshold for the entire patient cohort (n=203) in view of survival analyses (unpublished results). Subsequent multivariable survival analyses revealed that both D1C2 uniform positivity (OS: HR=1.825, p=0.019; DFS: HR=1.894, p=0.006) and ECD shedding (OS: HR = 1.856, p=0.016; DFS: HR = 1.808, p = 0.011) were independently associated with survival. This result illustrates that the developed scoring system in chapter 5 is clinically relevant, since there is a strong independent association of D1C2 uniform positivity and shedding in both a preselected (C-terminal MET positive) and more general (entire) patient population. Although it can be stated that membranous D1C2 uniform positivity and MET-EC- are associated with poor OS and DFS, future work is necessary to further optimize and validate these results using different inclusion criteria in an independent, more contemporary, patient cohort. Such work might lead to different optimal thresholds for survival analyses and a redefinition of patients diagnosed with OSCC likely to be eligible for MET targeted therapies, ultimately resulting in an updated version of the proposed CDx (chapter 4, 5, and 7). Is membranous MET immunoreactivity alone sufficient to predict susceptibility for MET targeted therapies? In retrospect, the assumption to only consider membranous MET immunoreactivity as a potential stratifier for MET targeted therapies was short sighted. It is known that upon ligand binding rapid internalization of phosphorylated MET takes place through clathrin-mediated endocytosis (34, 35). Originally, endosome-carried MET was assumed to be degraded through fusion with lysosomes (34, 36). However, following endocytosis, MET can be trafficked to the early endosome via the microtubule network, which is facilitated by protein kinase C alpha (PKCα) (35). From the early endosome phosphorylated MET enables sustained activation of ERK1/2 (37). Activated ERK1/2 is subsequently relocated to focal complexes at the plasma membrane (37, 38), which is mediated by protein kinase C epsilon (PKCε) (37). Ultimately, MET mediated ERK1/2 activation and its PKCε mediated membranous translocation facilitate HGF induced cell migration (39). Alternatively, in the absence of active PKCε, ERK1/2 is not directed to the plasma membrane. However, 8
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