Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling

J Zeilstra, S P J Joosten, H van Andel, C Tolg, A Berns, M Snoek, M van de Wetering, M Spaargaren, H Clevers, S T Pals

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

A gene signature specific for intestinal stem cells (ISCs) has recently been shown to predict relapse in colorectal cancer (CRC) but the tumorigenic role of individual signature genes remains poorly defined. A prominent ISC-signature gene is the cancer stem cell marker CD44, which encodes various splice variants comprising a diverse repertoire of adhesion and signaling molecules. Using Lgr5 as ISC marker, we have fluorescence-activated cell sorting-purified ISCs to define their CD44 repertoire. ISCs display a specific set of CD44 variant isoforms (CD44v), but remarkably lack the CD44 standard (CD44s) isoform. These CD44v also stand-out in transformed human ISCs isolated from microadenomas of familial adenomatous polyposis patients. By employing knock-in mice expressing either CD44v4-10 or CD44s, we demonstrate that the CD44v isoform, but not CD44s, promotes adenoma initiation in Apc(Min/+)mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.

Original languageEnglish
Pages (from-to)665-70
Number of pages6
JournalOncogene
Volume33
Issue number5
DOIs
Publication statusPublished - 30 Jan 2014

Keywords

  • Adenomatous Polyposis Coli
  • Animals
  • Antigens, CD44
  • Cell Transformation, Neoplastic
  • Flow Cytometry
  • Gene Expression Profiling
  • Gene Knock-In Techniques
  • Intestinal Neoplasms
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells
  • Protein Isoforms
  • Receptors, G-Protein-Coupled
  • Tumor Cells, Cultured
  • Wnt Signaling Pathway

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