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

Am J Pathol. 2000 Nov;157(5):1563-73. doi: 10.1016/S0002-9440(10)64793-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms / metabolism*
  • Heparan Sulfate Proteoglycans / metabolism*
  • Heparan Sulfate Proteoglycans / physiology
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Ligands
  • Phosphorylation
  • Prognosis
  • Proto-Oncogene Proteins c-met / metabolism*


  • CD44V3,8-10
  • Heparan Sulfate Proteoglycans
  • Hyaluronan Receptors
  • Ligands
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met