Distinct levels of radioresistance in Lgr5(+) colonic epithelial stem cells versus Lgr5(+) small intestinal stem cells Journal Article

Authors: Hua, G.; Wang, C.; Pan, Y.; Zeng, Z.; Lee, S. G.; Martin, M. L.; Haimovitz-Friedman, A.; Fuks, Z.; Paty, P. B.; Kolesnick, R.
Article 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. Employing Lgr5-lacZ transgenic mice and Lgr5 in situ hybridization, we found colonic epithelial stem cells (CESC) markedly more radioresistant in vivo than 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 doublestrand break (DSB) repair represents the sine qua non of 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. © 2017 American Association for Cancer Research.
Keywords: controlled study; unclassified drug; nonhuman; mitosis; animal cell; mouse; animal tissue; dna damage; cell survival; dna repair; animal experiment; in vivo study; in situ hybridization; chromosome aberration; ionizing radiation; cell cycle arrest; cell cycle checkpoint; radiosensitivity; double stranded dna break; small intestine; g protein coupled receptor; intestine mucosa; tissue reaction; crypt cell; intestinal stem cell; article; leucine rich repeat containing g protein coupled receptor 5; colon epithelium; colonic epithelial stem cell
Journal Title: Cancer Research
Volume: 77
Issue: 8
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2017-04-15
Start Page: 2124
End Page: 2133
Language: English
DOI: 10.1158/0008-5472.can-15-2870
PUBMED: 28202528
PROVIDER: scopus
PMCID: PMC5621135
Notes: Article -- Export Date: 2 June 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Zvi Fuks
    415 Fuks
  2. Philip B Paty
    419 Paty
  3. Zhaoshi Zeng
    86 Zeng
  4. Richard N Kolesnick
    277 Kolesnick
  5. Guoqiang Hua
    17 Hua
  6. Maria Laura Martin
    11 Martin
  7. Sang Gyu   Lee
    15 Lee
  8. Yan Pan
    1 Pan