TY - JOUR
T1 - Krt19+/Lgr5- Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine
AU - Asfaha, Samuel
AU - Hayakawa, Yoku
AU - Muley, Ashlesha
AU - Stokes, Sarah
AU - Graham, Trevor A.
AU - Ericksen, Russell E.
AU - Westphalen, Christoph B.
AU - Von Burstin, Johannes
AU - Mastracci, Teresa L.
AU - Worthley, Daniel L.
AU - Guha, Chandhan
AU - Quante, Michael
AU - Rustgi, Anil K.
AU - Wang, Timothy C.
N1 - Funding Information:
The authors thank the members of the Irving Cancer Research Center Core Microscopy Core Facility for their technical assistance and also thank Victor Lin of the Columbia Mouse Transgenic Core Facility for his help with generation of Krt19 -mApple mice. We thank Genentech for their generosity in providing the Lgr5 -GFP-DTR knockin mice used for this study. The authors additionally recognize the technical assistance of Yagnesh Tailor, Karan Nagar, Chintan Kapadia, and Kelly Betz. Dr. Samuel Asfaha was supported by a CIHR Clinician Scientist Phase I Award and an AHFMR Clinical Fellowship Award. This work was supported by the NIH (UO1 DK103155, R37 DK052778, and RO1 DK097016) (to T.C.W.). This work received grants from the NIH (R01 DK056645). Support was received from the Hansen Foundation and National Colon Cancer Research Alliance and the NIH (P30 DK 050306) (to A.K.R.) and its Mouse Core Facility.
Funding Information:
The authors thank the members of the Irving Cancer Research Center Core Microscopy Core Facility for their technical assistance and also thank Victor Lin of the Columbia Mouse Transgenic Core Facility for his help with generation of Krt19-mApple mice. We thank Genentech for their generosity in providing the Lgr5-GFP-DTR knockin mice used for this study. The authors additionally recognize the technical assistance of Yagnesh Tailor, Karan Nagar, Chintan Kapadia, and Kelly Betz. Dr. Samuel Asfaha was supported by a CIHR Clinician Scientist Phase I Award and an AHFMR Clinical Fellowship Award. This work was supported by the NIH (UO1 DK103155, R37 DK052778, and RO1 DK097016) (to T.C.W.). This work received grants from the NIH (R01 DK056645). Support was received from the Hansen Foundation and National Colon Cancer Research Alliance and the NIH (P30 DK 050306) (to A.K.R.) and its Mouse Core Facility.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/6/4
Y1 - 2015/6/4
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stem.2015.04.013
DO - 10.1016/j.stem.2015.04.013
M3 - Article
C2 - 26046762
AN - SCOPUS:84947806812
SN - 1934-5909
VL - 16
SP - 627
EP - 638
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 6
ER -
