Lineage Tracing Reveals Lgr5⁺ Stem Cell Activity in Mouse Intestinal Adenomas

Arnout G. Schepers,^* Hugo J. Snippert,^*, Daniel E. Stange, Maaike van den Born, Johan H. van Es, Marc van de Wetering, Hans Clevers

Abstract: The concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted great interest but remains controversial. Studying mouse models, we provide direct, functional evidence for the presence of stem cell activity within primary intestinal adenomas, a precursor to intestinal cancer. By "lineage retracing" using the multicolor Cre-reporter R26R-Confetti, we demonstrate that the crypt stem cell marker Lgr5 (leucine-rich repeat–containing heterotrimeric guanine nucleotide–binding protein–coupled receptor 5) also marks a subpopulation of adenoma cells that fuel the growth of established intestinal adenomas. These Lgr5⁺ cells, which represent about 5 to 10% of the cells in the adenomas, generate additional Lgr5⁺ cells as well as all other adenoma cell types. The Lgr5⁺ cells are intermingled with Paneth cells near the adenoma base, a pattern reminiscent of the architecture of the normal crypt niche.

Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen, and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.

Present address: Molecular Cancer Research, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands.

To whom correspondence should be addressed. E-mail: h.clevers{at}hubrecht.eu

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