Journal Article

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

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

2009

Overview

Intestinal cancer: stem-cell destinies Inappropriate activation of the Wnt signalling pathway in intestinal stem cells causes them to become cancerous. Two papers in this issue help identify the cell type at the root of this cancer, which should in turn aid therapeutic design. Zhu et al . report that prominin 1, a surface protein found on both normal stem cells and cancer stem cells, is a marker for stem cells that are prone to neoplastic transformation. Barker et al . show that in cells expressing Lgr5 , previously identified as a marker for intestinal stem cells, activation of Wnt signalling is sufficient to initiate tumour formation. Intestinal tumours can originate from Lgr5 + intestinal stem cells after genetic activation of the Wnt signalling pathway. 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 1 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Adenoma - genetics / Adenoma - metabolism / Adenoma - pathology / Adenomatous Polyposis Coli Protein - deficiency / Adenomatous Polyposis Coli Protein - genetics / Animal tumors. Experimental tumors / Animals / beta Catenin - metabolism / Biological and medical sciences / Cancer / Cell division / Cell Lineage / Cell Proliferation / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - pathology / Colonic Neoplasms - genetics / Colonic Neoplasms - metabolism / Colonic Neoplasms - pathology / Development and progression / Experimental digestive system and abdominal tumors / Gastrointestinal cancer / Genes, APC / Genetic aspects / Health aspects / Humanities and Social Sciences / Intestinal Neoplasms - genetics / Intestinal Neoplasms - metabolism / Intestinal Neoplasms - pathology / Intestine, Small / letter / Medical sciences / Methods / Mice / multidisciplinary / Mutation / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Properties / Receptors, G-Protein-Coupled - analysis / Receptors, G-Protein-Coupled - genetics / Receptors, G-Protein-Coupled - metabolism / Science / Science (multidisciplinary) / Small intestine / Stem cells / Tumors