PMID- 24763434
OWN - NLM
STAT- MEDLINE
DCOM- 20150731
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 4
DP  - 2014
TI  - Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
PG  - e96023
LID - 10.1371/journal.pone.0096023 [doi]
LID - e96023
AB  - Familial adenomatous polyposis (FAP) is often due to adenomatous polyposis coli 
      (APC) gene germline mutations. Somatic APC defects are found in about 80% of 
      colorectal cancers (CRCs) and adenomas. Rapamycin inhibits mammalian target of 
      rapamycin (mTOR) protein, which is often expressed in human adenomas and CRCs. We 
      sought to assess the effects of rapamycin in a mouse polyposis model in which 
      both Apc alleles were conditionally inactivated in colon epithelium. Two days 
      after inactivating Apc, mice were given rapamycin or vehicle in cycles of two 
      weeks on and two weeks off. Polyps were scored endoscopically. Mice were 
      euthanized at time points or when moribund, and tissue analyses were performed. 
      In other studies, mice with demonstrable Apc-defective colon polyps were given 
      rapamycin, followed by analysis of their colon tissues. The median survival of 
      mice receiving rapamycin treatment cycles was 21.5 versus 6.5 weeks in control 
      mice (p = 0.03), and rapamycin-treated mice had a significantly lower percentage 
      of their colon covered with polyps (4.3+/- 2 vs 56.5+/- 10.8 percent, p = 0.001). 
      Mice with Apc-deficient colon tissues that developed high grade dysplasia treated 
      with rapamycin underwent treatment for significantly longer than mice treated 
      with vehicle (15.8 vs 5.1 weeks, p = 0.003). In Apc-defective colon tissues, 
      rapamycin treatment was linked to decreased levels of beta-catenin and Sox9 at 7 
      weeks. Other effects of rapamycin in Apc-defectivecolon tissues included 
      decreased proliferation and increased numbers of differentiated goblet cells at 7 
      weeks. Rapamycin did not affect beta-catenin-regulated gene expression in cultured 
      intestinal epithelial cells. Rapamycin has potent inhibitory effects in a mouse 
      colon polyposis model, and mTOR inhibition is linked to decreased proliferation 
      and increased expression of differentiation markers in Apc-mutant colon 
      epithelium and delays development of dysplasia. Our findings highlight the 
      possibility that mTOR inhibitors may have relevance for polyposis inhibition 
      approaches in FAP patients.
FAU - Hardiman, Karin M
AU  - Hardiman KM
AD  - Department of Surgery, University of Michigan Medical School, Ann Arbor, 
      Michigan, United States of America.
FAU - Liu, Jianhua
AU  - Liu J
AD  - Department of Surgery, University of Michigan Medical School, Ann Arbor, 
      Michigan, United States of America.
FAU - Feng, Ying
AU  - Feng Y
AD  - Department of Internal Medicine, University of Michigan Medical School, Ann 
      Arbor, Michigan, United States of America.
FAU - Greenson, Joel K
AU  - Greenson JK
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, 
      Michigan, United States of America.
FAU - Fearon, Eric R
AU  - Fearon ER
AD  - Department of Internal Medicine, University of Michigan Medical School, Ann 
      Arbor, Michigan, United States of America; Department of Human Genetics, 
      University of Michigan Medical School, Ann Arbor, Michigan, United States of 
      America; Department of Pathology, University of Michigan Medical School, Ann 
      Arbor, Michigan, United States of America.
LA  - eng
GR  - P30 CA046592/CA/NCI NIH HHS/United States
GR  - R01 CA082223/CA/NCI NIH HHS/United States
GR  - R01CA082223-11A2/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140424
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adenomatous Polyposis Coli Protein)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (beta Catenin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adenomatous Polyposis Coli/drug therapy/*pathology
MH  - Adenomatous Polyposis Coli Protein/*genetics
MH  - Animals
MH  - Animals, Genetically Modified
MH  - Antibiotics, Antineoplastic/pharmacology/*therapeutic use
MH  - Cell Differentiation
MH  - Cell Line
MH  - Colon/drug effects/pathology
MH  - Colonic Polyps/*drug therapy/pathology
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Epithelial Cells/drug effects/metabolism
MH  - Humans
MH  - Intestinal Mucosa/cytology/drug effects/metabolism
MH  - Mice
MH  - SOX9 Transcription Factor/metabolism
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - Wnt Signaling Pathway
MH  - beta Catenin/metabolism
PMC - PMC3999114
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/04/26 06:00
MHDA- 2015/08/01 06:00
PMCR- 2014/04/24
CRDT- 2014/04/26 06:00
PHST- 2013/06/06 00:00 [received]
PHST- 2014/04/02 00:00 [accepted]
PHST- 2014/04/26 06:00 [entrez]
PHST- 2014/04/26 06:00 [pubmed]
PHST- 2015/08/01 06:00 [medline]
PHST- 2014/04/24 00:00 [pmc-release]
AID - PONE-D-13-23463 [pii]
AID - 10.1371/journal.pone.0096023 [doi]
PST - epublish
SO  - PLoS One. 2014 Apr 24;9(4):e96023. doi: 10.1371/journal.pone.0096023. eCollection 
      2014.