PMID- 24487592
OWN - NLM
STAT- MEDLINE
DCOM- 20140506
LR  - 20220409
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 124
IP  - 3
DP  - 2014 Mar
TI  - Long-lived intestinal tuft cells serve as colon cancer-initiating cells.
PG  - 1283-95
AB  - Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker 
      that has been proposed to identify quiescent and tumor growth-sustaining stem 
      cells. DCLK1(+) tuft cells are increased in inflammation-induced carcinogenesis; 
      however, the role of these cells within the gastrointestinal epithelium and their 
      potential as cancer-initiating cells are poorly understood. Here, using a 
      BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a 
      subpopulation of DCLK1(+) cells is extremely long lived and possesses rare stem 
      cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1(+) tuft 
      cells contribute to recovery following intestinal and colonic injury. 
      Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1(+) cells was 
      not sufficient to drive colonic carcinogenesis under normal conditions; however, 
      dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of 
      poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1(+) cells. 
      Importantly, colonic tumor formation occurred even when colitis onset was delayed 
      for up to 3 months after induced APC loss in DCLK1(+) cells. Thus, our data define 
      an intestinal DCLK1(+) tuft cell population that is long lived, quiescent, and 
      important for intestinal homeostasis and regeneration. Long-lived DCLK1(+) cells 
      maintain quiescence even following oncogenic mutation, but are activated by 
      tissue injury and can serve to initiate colon cancer.
FAU - Westphalen, C Benedikt
AU  - Westphalen CB
FAU - Asfaha, Samuel
AU  - Asfaha S
FAU - Hayakawa, Yoku
AU  - Hayakawa Y
FAU - Takemoto, Yoshihiro
AU  - Takemoto Y
FAU - Lukin, Dana J
AU  - Lukin DJ
FAU - Nuber, Andreas H
AU  - Nuber AH
FAU - Brandtner, Anna
AU  - Brandtner A
FAU - Setlik, Wanda
AU  - Setlik W
FAU - Remotti, Helen
AU  - Remotti H
FAU - Muley, Ashlesha
AU  - Muley A
FAU - Chen, Xiaowei
AU  - Chen X
FAU - May, Randal
AU  - May R
FAU - Houchen, Courtney W
AU  - Houchen CW
FAU - Fox, James G
AU  - Fox JG
FAU - Gershon, Michael D
AU  - Gershon MD
FAU - Quante, Michael
AU  - Quante M
FAU - Wang, Timothy C
AU  - Wang TC
LA  - eng
GR  - R01 NS015547/NS/NINDS NIH HHS/United States
GR  - CAPMC/CIHR/Canada
GR  - P30 ES002109/ES/NIEHS NIH HHS/United States
GR  - R01 NS012969/NS/NINDS NIH HHS/United States
GR  - R01 DK097016/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Diphtheria Toxin)
RN  - 0 (Lgr5 protein, mouse)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - EC 2.7.1.11 (Doublecortin-Like Kinases)
RN  - EC 2.7.11.1 (Dclk1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
SB  - IM
MH  - Adenocarcinoma/metabolism/*pathology
MH  - Animals
MH  - Cell Lineage
MH  - Cells, Cultured
MH  - Colon/immunology/innervation/*pathology
MH  - Colonic Neoplasms/metabolism/*pathology
MH  - Diphtheria Toxin/pharmacology
MH  - Doublecortin-Like Kinases
MH  - Homeostasis
MH  - Intestinal Mucosa/immunology/innervation/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred CBA
MH  - Mice, Knockout
MH  - Neoplastic Stem Cells/*physiology
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Receptors, G-Protein-Coupled/metabolism
PMC - PMC3934168
EDAT- 2014/02/04 06:00
MHDA- 2014/05/07 06:00
PMCR- 2014/02/03
CRDT- 2014/02/04 06:00
PHST- 2013/09/25 00:00 [received]
PHST- 2013/11/14 00:00 [accepted]
PHST- 2014/02/04 06:00 [entrez]
PHST- 2014/02/04 06:00 [pubmed]
PHST- 2014/05/07 06:00 [medline]
PHST- 2014/02/03 00:00 [pmc-release]
AID - 73434 [pii]
AID - 10.1172/JCI73434 [doi]
PST - ppublish
SO  - J Clin Invest. 2014 Mar;124(3):1283-95. doi: 10.1172/JCI73434.