Intestinal adenomas contain multipotent stem cells

• ▸ Schepers AG, Snippert HJ, Stange DE, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 2012;337:731–5.

The stem cell architecture of the normal intestinal crypt is becoming increasingly well-defined by new markers that delineate cells capable of multilineage differentiation in both mice and humans. The same cannot be said for the intestinal adenoma. It is an underappreciated fact that adenomas are composed of crypts whose structure only varies from normal crypts in that they are dysplastic. The question remains however; are adenomatous crypts populated by multipotent stem cells, possibly distinct from cancer stem cells that may populate a tumour once it has become invasive? Schepers et al have developed a novel method of ‘lineage retracing’ in mice that have Apc depleted in Lgr5 knock-in stem cells which goes some way to answer this. The authors created a cross between ROSA26R-Confetti mice (a mouse that expresses different fluorescent proteins depending on the orientation of the transgene after Cre recombination induced by β-naphthoflavone) with Lgr5^{EGFP-Ires-CreERT2}/Apc^fl/fl conditional knock-in mice. Upon β-naphthoflavone injection, they discovered that adenoma crypts were lineage-labeled demonstrating that Lgr5-EGFP stem cells were capable of producing dysplastic differentiated progeny, and the transcriptional profile of these cells was found to be the same as Lgr5+ cells from normal mice. Furthermore, upon a subsequent β-naphthoflavone injection a new fluorescent colour developed indicating that a single Lgr5+ stem cell had undergone self renewal and that daughter Lgr5+ stem cells had repopulated the crypt. This is unequivocal evidence for the presence of multipotent stem cells in an adenoma that appear no different to stem cells within normal crypts and are capable of maintaining an adenoma. Importantly, the authors crossed in an inducible oncogenic K-ras forming an Lgr5^{EGFP-Ires-CreERT2}/Apc^fl/fl/Kras^{lsl-G12D …}