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 aden...

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Autores principales:	Karin M Hardiman, Jianhua Liu, Ying Feng, Joel K Greenson, Eric R Fearon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bc62b423af1d46478dfd2895a237726f
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spelling	oai:doaj.org-article:bc62b423af1d46478dfd2895a237726f2021-11-18T08:21:33ZRapamycin inhibition of polyposis and progression to dysplasia in a mouse model.1932-620310.1371/journal.pone.0096023https://doaj.org/article/bc62b423af1d46478dfd2895a237726f2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24763434/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Familial 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.Karin M HardimanJianhua LiuYing FengJoel K GreensonEric R FearonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e96023 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karin M Hardiman Jianhua Liu Ying Feng Joel K Greenson Eric R Fearon Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
description	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.
format	article
author	Karin M Hardiman Jianhua Liu Ying Feng Joel K Greenson Eric R Fearon
author_facet	Karin M Hardiman Jianhua Liu Ying Feng Joel K Greenson Eric R Fearon
author_sort	Karin M Hardiman
title	Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
title_short	Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
title_full	Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
title_fullStr	Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
title_full_unstemmed	Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
title_sort	rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/bc62b423af1d46478dfd2895a237726f
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Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model.

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