title: Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine.
abstract: 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.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Ashlesha
authors.initials: A
authors.lastname: Muley
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stokes
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, London EC1M 6BQ, UK.
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Graham
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ericksen
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Burstin
authors.affiliation: Department of Genetics and Development, Columbia University, New York, NY 10032, USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Mastracci
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, New York, NY 10467, USA.
authors.forename: Chandhan
authors.initials: C
authors.lastname: Guha
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.affiliation: Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D003106:Colon / Q000473:pathology*; D007422:Intestines / Q000473:pathology*; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D053539:Keratin-19; C493597:Lgr5 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled