PMID- 19092804
OWN - NLM
STAT- MEDLINE
DCOM- 20090311
LR  - 20250214
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Linking)
VI  - 457
IP  - 7229
DP  - 2009 Jan 29
TI  - Crypt stem cells as the cells-of-origin of intestinal cancer.
PG  - 608-11
LID - 10.1038/nature07602 [doi]
AB  - Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such 
      as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has 
      remained elusive. In a previously established Lgr5 (leucine-rich-repeat 
      containing G-protein-coupled receptor 5) knockin mouse model, a 
      tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem 
      cells. Here we show that deletion of Apc in these stem cells leads to their 
      transformation within days. Transformed stem cells remain located at crypt 
      bottoms, while fuelling a growing microadenoma. These microadenomas show 
      unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The 
      distribution of Lgr5(+) cells within stem-cell-derived adenomas indicates that a 
      stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. 
      When Apc is deleted in short-lived transit-amplifying cells using a different cre 
      mouse, the growth of the induced microadenomas rapidly stalls. Even after 
      30weeks, large adenomas are very rare in these mice. We conclude that 
      stem-cell-specific loss of Apc results in progressively growing neoplasia.
FAU - Barker, Nick
AU  - Barker N
AD  - Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 
      8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands.
FAU - Ridgway, Rachel A
AU  - Ridgway RA
FAU - van Es, Johan H
AU  - van Es JH
FAU - van de Wetering, Marc
AU  - van de Wetering M
FAU - Begthel, Harry
AU  - Begthel H
FAU - van den Born, Maaike
AU  - van den Born M
FAU - Danenberg, Esther
AU  - Danenberg E
FAU - Clarke, Alan R
AU  - Clarke AR
FAU - Sansom, Owen J
AU  - Sansom OJ
FAU - Clevers, Hans
AU  - Clevers H
LA  - eng
GR  - G0301154/MRC_/Medical Research Council/United Kingdom
GR  - CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081217
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adenomatous Polyposis Coli Protein)
RN  - 0 (Lgr5 protein, mouse)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (beta Catenin)
SB  - IM
MH  - Adenoma/genetics/metabolism/pathology
MH  - Adenomatous Polyposis Coli Protein/*deficiency/*genetics
MH  - Animals
MH  - *Cell Lineage
MH  - Cell Proliferation
MH  - *Cell Transformation, Neoplastic/genetics/pathology
MH  - Colonic Neoplasms/genetics/metabolism/pathology
MH  - Genes, APC
MH  - Intestinal Neoplasms/*genetics/metabolism/*pathology
MH  - Mice
MH  - Neoplastic Stem Cells/metabolism/*pathology
MH  - Receptors, G-Protein-Coupled/analysis/genetics/metabolism
MH  - beta Catenin/metabolism
EDAT- 2008/12/19 09:00
MHDA- 2009/03/12 09:00
CRDT- 2008/12/19 09:00
PHST- 2008/07/04 00:00 [received]
PHST- 2008/10/31 00:00 [accepted]
PHST- 2008/12/19 09:00 [entrez]
PHST- 2008/12/19 09:00 [pubmed]
PHST- 2009/03/12 09:00 [medline]
AID - nature07602 [pii]
AID - 10.1038/nature07602 [doi]
PST - ppublish
SO  - Nature. 2009 Jan 29;457(7229):608-11. doi: 10.1038/nature07602. Epub 2008 Dec 17.