In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2882-2882
Abstract:
Despite a well-characterized epidemiological association, mechanisms underlying the relationship between obesity and colorectal cancer remain incompletely defined. An emerging paradigm suggests that colorectal cancer arises through silencing of the GUCY2C tumor suppressor by loss of the hormone guanylin, a gene product universally lost in colorectal cancer. The present studies demonstrate that obesity is linked to colorectal cancer through suppression of guanylin expression, resulting in silencing of the GUCY2C tumor suppressor and epithelial dysfunction underlying tumorigenesis. In mice, obesogenic diets suppress the expression of guanylin protein, silencing GUCY2C and increasing epithelial dysfunction including DNA damage, crypt hyperproliferation and metabolic reprogramming, associated with amplification of colorectal tumorigenesis. Mouse models uncoupling caloric intake and weight revealed that suppression of guanylin by obesogenic diets reflected ingested calories, rather than the endocrine, adipokine and inflammatory milieu associated with obesity. Further, suppression of guanylin expression by obesogenic diets in wild type mice could be reversed by switching to a lean diet. Importantly, genetically enforced tissue-specific expression of guanylin eliminated epithelial dysfunction and colorectal tumorigenesis in transgenic mice. Taken together, the present studies highlight the guanylin-GUCY2C axis as a principle mechanistic link between colorectal cancer and the increased caloric intake characterizing obesity. Moreover, they highlight a unique opportunity to prevent colorectal cancer in obese patients by oral replacement with FDA-approved GUCY2C ligands. Citation Format: Erik S. Blomain, Jieru E. Lin, Francheska Colón-González, Gilbert W. Kim, Terry Hyslop, Tingting Zhan, Adam E. Snook, Scott A. Waldman. Calorie-induced silencing of the tumor suppressive guanylin-GUCY2C paracrine axis underlies colorectal cancer in obesity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2882. doi:10.1158/1538-7445.AM2015-2882
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-2882
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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