Crypt stem cells as the cells-of-origin of intestinal cancer

Nick Barker, Rachel A. Ridgway, Johan H. Van Es, Marc Van De Wetering, Harry Begthel, Maaike Van Den Born, Esther Danenberg, Alan R. Clarke, Owen J. Sansom, Hans Clevers

Research output: Contribution to journalArticlepeer-review

1797 Citations (Scopus)

Abstract

Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5+ cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.

Original languageEnglish
Pages (from-to)608-611
Number of pages4
JournalNature
Volume457
Issue number7229
DOIs
Publication statusPublished - 29 Jan 2009
Externally publishedYes

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