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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 28, 2016; 22(36): 8070-8077
Published online Sep 28, 2016. doi: 10.3748/wjg.v22.i36.8070
Guanylyl cyclase C signaling axis and colon cancer prevention
Amanda M Pattison, Dante J Merlino, Erik S Blomain, Scott A Waldman
Amanda M Pattison, Dante J Merlino, Erik S Blomain, Scott A Waldman, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
Author contributions: Pattison AM designed and composed the manuscript; Merlino DJ and Blomain ES helped compile, edit, and revise the manuscript; Waldman SA devised the manuscript content, oversaw manuscript preparation, and participated as the scientific advisor; all authors provided final approval of the version submitted and any revised versions.
Supported by NIH, No. R01CA170533, No. R01CA206026 and No. P30CA56036; and Targeted Diagnostic and Therapeutics, Inc.; a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows from the NIH, No. CA180500 (To Blomain ES); a Ruth L. Kirschstein National Research Service Award for Individual Predoctoral MD/PhD Fellows from the NIH, No. F30 DK103492 (To Merlino DJ); and a Predoctoral Fellowship in Pharmacology/Toxicology from the PhRMA Foundation.
Conflict-of-interest statement: Waldman SA is the Chair (uncompensated) of the Scientific Advisory Board of Targeted Diagnostics and Therapeutics, Inc. which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Scott A Waldman, MD, PhD, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 132 South 10th Street, 1170 Main, Philadelphia, PA 19107, United States. scott.waldman@jefferson.edu
Telephone: +1-215-9555693 Fax: +1-215-9555681
Received: March 25, 2016
Peer-review started: March 26, 2016
First decision: May 12, 2016
Revised: June 25, 2016
Accepted: August 1, 2016
Article in press: August 1, 2016
Published online: September 28, 2016
Processing time: 184 Days and 9.2 Hours
Abstract

Colorectal cancer (CRC) is a major cause of cancer-related mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. Guanylyl cyclase C (GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin (GUCA2A) and uroguanylin (GUCA2B), which bind and activate GUCY2C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C’s role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2C ligand linaclotide (Linzess™). Here we review the known contributions of the GUCY2C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

Keywords: Colorectal cancer; Guanylin; Uroguanylin; Chemoprevention; Heat-stable enterotoxins; Cyclic guanosine monophosphate; Guanylyl cyclase C

Core tip: Guanylyl cyclase C (GUCY2C) is a tissue-specific transmembrane receptor found in apical membranes of intestinal enterocytes that drives intestinal homeostatic mechanisms and opposes colorectal tumorigenesis. The receptor’s endogenous hormone ligands, guanylin and uroguanylin, are the most commonly lost gene products in colorectal cancer, making GUCY2C a potential therapeutic target for tumor prevention through hormone replacement therapy.