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

Oncogene volume 33, pages 665–670 (2014)Cite this article

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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 ApcMin/+mice. Our data identify CD44v as component of the ISCs program critical for tumor initiation, and as potential treatment target in CRC.

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Acknowledgements

This work was supported by a grant from the Dutch Cancer Society. The authors declare no competing financial interests.

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Author notes

  1. J Zeilstra and S P J Joosten: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    J Zeilstra, S P J Joosten, H van Andel, M Spaargaren & S T Pals

  2. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    C Tolg, A Berns & M Snoek

  3. Hubrecht Institute and University Medical Center Utrecht, Utrecht, The Netherlands

    M van de Wetering & H Clevers

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  1. J Zeilstra
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  2. S P J Joosten
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Correspondence to S T Pals.

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Zeilstra, J., Joosten, S., van Andel, H. et al. Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene 33, 665–670 (2014). https://doi.org/10.1038/onc.2012.611

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  • DOI: https://doi.org/10.1038/onc.2012.611

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