Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer

In colorectal cancer patients, prognosis is not determined by the primary t umor but by the formation of distant metastases, Molecules that have been i mplicated in the metastatic process are the proto-oncogene product c-Mct an d CD44 glycoproteins. Recently, we obtained evidence for functional collabo ration between these two molecules: CD44 Isoforms decorated with heparan su lfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility f actor hepatocyte growth factor/scatter factor (HGF/SF). This interaction st rongly promotes signaling through the receptor tyrosine kinase c-Met, In th e present study, we explored the expression of CD44-HS, c-Met, and HGF/SF i n the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms,which contain a site for NS attachment, a nd c-Met, were both overexpressed on the neoplastic epithelium of colorecta l adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increa sed levels in tumor tissue. On all tested colorectal cancer cell lines CD44 v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Wes tern. blotting, CD44 on these cells lines was decorated with IIS. Interacti on with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-in duced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prog nosis In patients with invasive colorectal carcinomas. Taken together, our findings Indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overex pressed In colorectal cancer and that HS moieties promote c-Met signaling i n colon carcinoma cells. These observations suggest that collaboration betw een CD44-HS and the c-Met signaling pathway may play an important role In c olorectal tumorigenesis.