摘要
Colorectal cancer(CRC) is a major cause of cancerrelated 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 GUCY2 C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2 C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2 C 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 GUCY2 C ligand linaclotide(Linzess^(TM)). Here we review the known contributions of the GUCY2 C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.
Colorectal cancer（CRC） is a major cause of cancerrelated 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 GUCY2 C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2 C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2 C 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 GUCY2 C ligand linaclotide(LinzessTM). Here we review the known contributions of the GUCY2 C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.
基金
Supported by NIH,No.R01CA170533,No.R01CA206026 and No.P30CA56036
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)
a Predoctoral Fellowship in Pharmacology/Toxicology from the PhR MA Foundation
