In Situ Validation of an Intestinal Stem Cell Signature in Colorectal Cancer
Jennifer L Ziskin, Debra Dunlap, Murat Yaylaoglu, William F Forrest, Hartmut Koeppen, Adrian M Jubb. Stanford University Medical Center, Stanford, CA; Genentech Inc., South San Francisco, CA
Background: Wnt/Tcf, Lgr5, Ascl2 and/or Bmi1 signaling are believed to define the mouse intestinal stem cell niche(s) from which adenomas arise. However, there is insufficient evidence that these observations are relevant to human colorectal adenocarcinomas. The aim of this study was to determine the relevance of these putative intestinal stem cell markers to human colorectal cancer using in situ hybridization.
Design: Nineteen 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 hybridization in 57 colorectal adenocarcinomas. Multiplex fluorescent in situ hybridization was also performed for Ascl2/Lgr5/Olfm4.
Results: Ascl2 and Lgr5 were expressed in 85 and 76% of cancers respectively, and expression of Ascl2 and Lgr5 was positively correlated (p=0.003). Expression of Bmi1 was observed in 48% of cancers, but expression was very weak in 92% of cases with expression. Both Ascl2 and Lgr5 were positively correlated with expression of Axin2, Cdca7, Dkc1, EphB2, EphB3, Ets2, Rnf43, Sox9 and Znrf3, but neither were correlated with expression of Cdk6, Gpx2, Olfm4 or Tnfrsf19.
Conclusions: These data suggest that 76-85% of colorectal cancers show a Lgr5/Ascl2 intestinal stem cell signature and support the hypothesis that a large proportion derive from crypt stem cells. In addition, the results demonstrate that not all stem cell markers in mouse small intestine are relevant to human colorectal cancer. Finally, the predominantly uniform expression patterns of Ascl2, Lgr5 and EphB2 suggest that intestinal stem cell genes may not mark tumour-initiating cells.
Monday, March 19, 2012 1:00 PM
Poster Session II # 119, Monday Afternoon