KNAW Repository

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

Barker, N. and Ridgway, R.A. and Es van, J.H. and Wetering van de, M.L. and Begthel, H.L. and Born van den, M.M.W. and Danenberg, E.M. and Clarke, A.R. and Sansom, O.J. and Clevers, H. (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature, 457, 608-11. ISSN 0028-0836.

Full text not available from this repository.

Official URL: http://depot.knaw.nl/6941

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.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:6941
Deposited On:15 Dec 2009 01:00
Last Modified:10 Aug 2011 14:57

Repository Staff Only: item control page