Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance

Sander P J Joosten, Marcel Spaargaren, Hans Clevers, Steven T Pals

Research output: Contribution to journal/periodicalBook/Film/Article reviewScientific

Abstract

Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which collectively drive malignant transformation in colorectal cancer (CRC). However, the contribution of individual genes to intestinal homeostasis and tumorigenesis often is incompletely defined. Here, we discuss converging evidence indicating that the receptor tyrosine kinase (RTK) MET and its ligand hepatocyte growth factor (HGF) play a major role in the intestinal damage response, as well as in intestinal tumorigenesis, by controlling the proliferation, survival, motility, and stemness of normal and neoplastic intestinal epithelial cells. These activities of MET are promoted by specific CD44 isoforms expressed by ISCs. The accrued data indicate that MET and the EGFR have overlapping roles in the biology of intestinal epithelium and that metastatic CRCs can exploit this redundancy to escape from EGFR-targeted treatments, co-opting HGF/MET/CD44v signalling. Hence, targeting both pathways may be required for effective treatment of (a subset of) CRCs. The RTK identity of MET, the distinctive 'plasminogen-like' structure and activation mode of its ligand HGF, and the specific collaboration of MET with CD44, provide several unique targeting options, which merit further exploration.

Original languageEnglish
Pages (from-to)188437
JournalBiochimica et biophysica acta. Reviews on cancer
Volume1874
Issue number2
DOIs
Publication statusPublished - Dec 2020

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