240 Chapter 8 in OSCC through parallel use of reliable C- and N-terminal MET moAbs (D1C2 and A2H2-3, chapter 4). This was confirmed in vitro through (1) detection of C-terminal fragments, that are expected to be the result of shedding (supplementary table 5, chapter 4), under reducing conditions and (2) detection of N-terminal fragments in the culture medium by performing an ELISA. The detection of (1) C-terminal fragments in FF tissues under reducing conditions and (2) areas that are positive for D1C2, yet devoid of A2H2-3, membranous MET immunoreactivity (MET-EC-) across FFPE tissues, both derived from surgically removed primary OSCC, illustrated that ectodomain shedding can be detected in tumor specimens. As MET-EC- might stabilize and therefore undergo activation on the membrane (68) of OSCC following (GPCR) transactivation of (EGFR) signaling, and/or overexpression of ADAM10/17 and/or MET, possibly resulting in invasive growth (chapter 7), and is associated with poor prognosis (chapters 4 and 5); it was concluded that combining C- and N-terminal MET immunoreactivity in a diagnostic setting might aid in the stratification of patients eligible for treatment with MET targeted therapies (chapter 4, 5, and 7). Moreoever, MET-EC- might have an impact on the choice of type of MET targeted therapy, namely moAb and/or TKIs, or treatment strategies directed against proteins that orchestrate ectodomain shedding, such as ADAMs (69, 70) (chapters 4, 5, and 7). Taking everything into consideration, it is concluded here that MET-EC- should be incorporated in the design of CDx to improve patient stratification and ultimately prolong survival. Does C-terminal MET uniform positivity has potential added value in clinical decision making on elective neck dissection? As MET orchestrates the program of invasive growth (20, 29, 30), and thus facilitates the dissemination of cancers cells, we investigated whether C-terminal MET uniform positivity on WTSs is associated with the presence of RLNM (pN+ and occult) in early OSCC. After confirming that this was the case, we hypothesized on the potential added value of C-terminal MET uniform positivity in clinical decision making on END with respect to DOI > 4 mm, which is used to in making the decision to perform an END within the Erasmus MC (71-73) (chapter 6). C-terminal MET uniform positivity was found to be significantly associated with RLNM (pN+ and occult) in early OSCC, outperforming DOI. Although binary logistic regression analysis illustrated that only C-terminal MET uniform positivity
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