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In situ validation of an intestinal stem cell signature in colorectal cancer
  1. Jennifer L Ziskin1,
  2. Debra Dunlap2,
  3. Murat Yaylaoglu2,
  4. Imola K Fodor3,
  5. William F Forrest3,
  6. Rajesh Patel4,
  7. Nianfeng Ge2,
  8. Gordon G Hutchins5,
  9. James K Pine5,
  10. Philip Quirke5,
  11. Hartmut Koeppen2,
  12. Adrian M Jubb2
  1. 1Department of Pathology, Stanford University Medical Center, Stanford, California, USA
  2. 2Department of Pathology, Genentech Inc, South San Francisco, California, USA
  3. 3Department of Biostatistics, Genentech Inc, South San Francisco, California, USA
  4. 4Department of Oncology Diagnostics, Genentech Inc, South San Francisco, California, USA
  5. 5Department of Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, St James' University Hospital, Leeds, UK
  1. Correspondence to Dr A M Jubb, Department of Pathology, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA; adrianj{at}gene.com

Abstract

Objective Wnt/Tcf, Lgr5, Ascl2 and/or Bmi1 signalling is believed to define the mouse intestinal stem cell niche(s) from which adenomas arise. The aim of this study was to determine the relevance of these putative intestinal stem cell markers to human colorectal cancer.

Design 19 putative intestinal stem cell markers, including Ascl2 and Lgr5, were identified from published data and an evaluation of a human colorectal gene expression database. Associations between these genes were assessed by isotopic in situ hybridisation (ISH) in 57 colorectal adenocarcinomas. Multiplex fluorescent ISH and chromogenic non-isotopic ISH were performed to confirm expression patterns. The prognostic significance of Lgr5 was assessed in 891 colorectal adenocarcinomas.

Results Ascl2 and Lgr5 were expressed in 85% and 74% of cancers respectively, and expression was positively correlated (p=0.003). Expression of Bmi1 was observed in 47% of cancers but was very weak in 98% of cases with expression. Both Ascl2 and/or Lgr5 were positively correlated with the majority of genes in the signature but neither was correlated with Cdk6, Gpx2, Olfm4 or Tnfrsf19. Lgr5 did not have prognostic significance.

Conclusion These data suggest that 74–85% of colorectal cancers express a Lgr5/Ascl2 associated signature and support the hypothesis that they derive from Lgr5+/Ascl2+ crypt stem cells, not Bmi1+ stem cells. However, Olfm4 was not found to be a useful marker of Lgr5+ cells in normal colon or tumours. In this large series, Lgr5 expression is not associated with increased tumour aggressiveness, as might be expected from a cancer stem cell marker.

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Footnotes

  • HK and AMJ contributed equally to this paper.

  • Funding This research was funded by Genentech Inc.

  • Competing interests DD, IKF, MY, RP, WFF, HK and AMJ are employees of Genentech Inc and hold equity in Roche. JLZ was formerly an employee of Genentech Inc.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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