title: Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer.
abstract: In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in 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 HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: V J
authors.initials: VJ
authors.lastname: Wielenga
authors.forename: R
authors.initials: R
authors.lastname: van der Voort
authors.forename: T E
authors.initials: TE
authors.lastname: Taher
authors.forename: L
authors.initials: L
authors.lastname: Smit
authors.forename: E A
authors.initials: EA
authors.lastname: Beuling
authors.forename: C
authors.initials: C
authors.lastname: van Krimpen
authors.forename: M
authors.initials: M
authors.lastname: Spaargaren
authors.forename: S T
authors.initials: ST
authors.lastname: Pals
mesh_terms: D015179:Colorectal Neoplasms / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism* / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008024:Ligands; D010766:Phosphorylation; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
chemical_list: C121450:CD44V3,8-10; D019812:Heparan Sulfate Proteoglycans; D018960:Hyaluronan Receptors; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met