Ectodomain shedding unleashes the aggressive nature of the MET
oncogene product. Using specific C- and N-terminal MET
antibodies (D1C2 and A2H2-3), MET
protein status (i.e., no MET, decoy MET, transmembranous C-terminal MET with or without the ectodomain) was investigated in
oral squamous cell carcinoma. For the
cancers showing transmembranous C-terminal MET, the impact of ectodomain shedding on prognosis was investigated. To examine ectodomain shedding, reduced lysates of
oral squamous cell carcinoma cell lines were immunoblotted using D1C2 and an ELISA was performed on
culture media using A2H2-3. In addition, reduced lysates of fresh frozen tissues of 30
oral squamous cell carcinoma were immunoblotted using D1C2 and immunohistochemistry was performed on corresponding
formalin-fixed
paraffin-embedded tissues using both
antibodies on parallel sections. To examine MET
protein status, differences between membranous D1C2 and A2H2-3 immunoreactivities were scored using parallel tissue microarray sections representing 156
oral squamous cell carcinoma. The prognostic value of ectodomain shedding was examined using Cox regression analysis for disease-free survival and overall survival. Ectodomain shedding was observed in all cell lines, 43% (n = 13) of fresh frozen and 50% (n = 15) of
formalin-fixed
paraffin-embedded
cancers (27% overlap, n = 8). The tissue microarray showed no MET in 23% (n = 36), decoy MET in 9% (n = 14), and transmembranous C-terminal MET in 68% (n = 106) of examined
cancers. Within the latter group, ectodomain shedding occurs in 36% (n = 38) of the cases and is independently associated with poor disease-free survival (HR = 2.41; 95% CI, 1.35-4.30 and P = 0.003)-though not overall survival (HR = 1.64; 95% CI, 0.92-2.94 and P = 0.095)-after correcting for factors known to influence survival. In conclusion, MET ectodomain shedding occurs in transmembranous C-terminal MET positive
oral squamous cell carcinoma and is independently associated with disease-free survival. These findings might aid in designing companion diagnostics for targeted
therapies directed against MET.