Krt19+/Lgr5− Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine

• Published in: Cell stem cell Vol. 16; no. 6; pp. 627 - 638
• Main Authors: Asfaha, Samuel, Hayakawa, Yoku, Muley, Ashlesha, Stokes, Sarah, Graham, Trevor A., Ericksen, Russell E., Westphalen, Christoph B., von Burstin, Johannes, Mastracci, Teresa L., Worthley, Daniel L., Guha, Chandhan, Quante, Michael, Rustgi, Anil K., Wang, Timothy C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2015
• Subjects: Animals; Colon - pathology; Intestines - pathology; Keratin-19 - genetics; Keratin-19 - metabolism; Mice, Transgenic; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Radiation Tolerance; Receptors, G-Protein-Coupled - metabolism; RNA Transport; RNA, Messenger - genetics; RNA, Messenger - metabolism
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2015.04.013

Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5+ cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5− stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5+ CBCs in the colon and intestine. In colorectal cancer models, Krt19+ cancer-initiating cells are also radioresistant, while Lgr5+ stem cells are radiosensitive. Moreover, Lgr5+ stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5+ stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19+ stem cells are a discrete target relevant for cancer therapy. [Display omitted] •Krt19 marks long-lived colonic and intestinal stem cells above the crypt base•Krt19 stem cells render Lgr5+ CBCs dispensable in colon and intestine•Radioresistant Krt19+ cancer-initiating cells are distinct from Lgr5+ cells•Lgr5+ cancer stem cells are dispensable in Krt19+ cell-derived APC floxed tumors Genetic-inducible fate-mapping studies suggest that intestinal epithelial cells are replaced from at least two principal stem cell pools. Asfaha et al. now identify Krt19+ cells in the colon that are long-lived, radioresistant cancer-initiating stem cells distinct from the previously described radiosensitive Lgr5+ stem cells.