title: Distinct Levels of Radioresistance in Lgr5+Colonic Epithelial Stem Cells versus Lgr5+Small Intestinal Stem Cells.
abstract: Although small and large intestines possess seemingly similar Wnt-driven leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)+adult epithelial stem cells, we report here that the two organs exhibit distinct mechanisms of tissue response to ionizing radiation. EmployingLgr5-lacZtransgenic mice and Lgr5in situhybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistantin vivothan small intestinal crypt base columnar stem cells (CBC; D0= 6.0 ± 0.3 Gy vs. 1.3 ± 0.1, respectively;P< 0.01). Accordingly, CESCs survived 30 Gy exposure, while CBCs were completely depleted after 15 Gy. EdU incorporation studies indicated that after 19 Gy, CBCs exited growth arrest at 12 hours, resuming normal mitotic activity despite 60% of this population displaying residual γH2AX foci, indicative of persistent unrepaired DNA damage. Checkpoint recovery before complete double-strand break (DSB) repair represents thesine qua nonof a newly defined potentially lethal pathophysiology termed checkpoint adaptation. In the small intestinal mucosa, checkpoint adaptation resulted in CBCs succumbing to an 8-fold increase in the incidence of highly lethal chromosomal aberrations and mitotic catastrophe by 48 hours postradiation. In contrast, Lgr5+CESCs displayed delayed checkpoint recovery at 48 hours post-19 Gy, coordinated with complete DSB repair and regeneration of colonic mucosa originating, at least in part, from surviving CESCs. The discovery that small intestinal CBCs succumb to checkpoint adaptation is the first demonstration that this aberrant cell-cycle response may drive mammalian tissue radiosensitivity.Cancer Res; 77(8); 2124-33. ©2017 AACR.
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China. r-kolesnick@ski.mskcc.org guoqianghua@fudan.edu.cn.|Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.
authors.forename: Chu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Radiation Medicine, Fudan University, Shanghai, China.|Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Yan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sang Gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Martin
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Fuks
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.affiliation: Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, New York. r-kolesnick@ski.mskcc.org guoqianghua@fudan.edu.cn.
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
mesh_terms: D000818:Animals; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011836:Radiation Tolerance / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D014916:Whole-Body Irradiation
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled