Up-regulated Expression of ADAM17 in Human Colon Carcinoma: Co-expression with EGFR in Neoplastic and Endothelial Cells

The ADAM17 metalloproteinase (a disintegrin and metalloprotease 17) controls epidermal growth factor receptor (EGFR) activation through regulated shedding of EGFR ligands. With the advent of new therapeutic options targeting EGFR signalling in colon carcinoma, it was decided to determine ADAM17 status in relation to clinico-pathological parameters and EGFR status. To this end, a series of 39 colon carcinomas were analysed. Immunohistochemistry and immunofluorescence were used to localize ADAM17, EGFR, and the activated forms of EGFR. The activated form of ADAM17 was assessed in primary cancers and colon cell lines by immunoblotting. ADAM17 and EGFR mRNA levels were assessed by quantitative RT-PCR. Chromogenic in situ hybridization (CISH) was used to quantify the HER1 gene. ADAM17 was strongly expressed in all tumours, by both neoplastic and endothelial cells. It was expressed both as a pro- and as an active form in tumours and colonic cancer cell lines. ADAM17 mRNA was up-regulated in 90% of colon carcinomas relative to the paired normal mucosa, whatever the tumour grade or stage. When present, activated EGFR was co-expressed with ADAM17 by colon carcinomas, although at a variable level among tumour cells, and by endothelial cells. EGFR mRNA was overexpressed in 77% of colon carcinomas compared with the paired normal mucosa. One case showed high-level amplification of HER1. In conclusion, this study is the first demonstration that ADAM17 is overexpressed in human primary colon carcinoma, whatever the tumour stage and differentiation and whatever the level of EGFR expression. Its co-expression with EGFR, in both neoplastic and endothelial cells, suggests a role for ADAM17 in tumour growth and angiogenesis.