Abstract
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.
Highlights
One of the major clinical challenges in most patients with familial adenomatous polyposis (FAP) is the development of thousands of colorectal adenomas which can progress to carcinoma without proctocolectomy
The primary means by which adenomatous polyposis coli (APC) inactivation contributes to colon adenoma and colorectal cancers (CRCs) development is believed to be the resultant dysregulation in the levels and localization of the b-catenin protein, the role of nuclear b-catenin as a binding partner for the T cell factor (TCF) family of transcription factors and the function of b-catenin/TCF complexes as key regulators of the expression of certain genes [1]
In TAM-induced, Apc-mutant adenomatous crypts of CDX2P-CreERT2 Apcfl/fl mice, we found that Alcian blue staining was largely absent, and RAP treatment restored some of the differentiated goblet cells in Apc-mutant adenomatous crypts, albeit not entirely to the numbers seen in control colon epithelium (N = 5) (Figure 5D)
Summary
One of the major clinical challenges in most patients with familial adenomatous polyposis (FAP) is the development of thousands of colorectal adenomas which can progress to carcinoma without proctocolectomy. The primary means by which APC inactivation contributes to colon adenoma and CRC development is believed to be the resultant dysregulation in the levels and localization of the b-catenin protein, the role of nuclear b-catenin as a binding partner for the T cell factor (TCF) family of transcription factors and the function of b-catenin/TCF complexes as key regulators of the expression of certain genes [1]. Rapamycin (RAP) is an inhibitor of the mammalian target of rapamycin protein (mTOR) which is strongly expressed in mouse small intestine polyps with Apc defects [2] and in human colorectal adenomas and CRCs [3]. A downstream phosphorylation target and likely physiological effector of mTOR signaling, the S6 ribosomal protein, shows increased phosphorylation (phospho-S6) in roughly 40 percent of colorectal carcinomas (CRCs) and adenomas [4]. mTOR regulates cell growth, proliferation, and motility and inhibition inhibits cancer development or growth in various models [5,6]
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