Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
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 β-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 β-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.
Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Karin M
KM
Hardiman
Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Jianhua
J
Liu
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Ying
Y
Feng
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Joel K
JK
Greenson
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.
Eric R
ER
Fearon
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy / Q000473:pathology*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003111:Colonic Polyps / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D055758:SOX9 Transcription Factor / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D000903:Antibiotics, Antineoplastic; D055758:SOX9 Transcription Factor; D051176:beta Catenin; D020123:Sirolimus