Colorectal Cancer Is a Paracrine Deficiency Syndrome Amenable to Oral Hormone Replacement Therapy

• Published in: Clinical and translational science 2008-09, Vol.1 (2), p.163-167
• Main Authors: Li, Peng, Lin, Jieru E., Snook, Adam E., Gibbons, Ahmara V., Zuzga, David S., Schulz, Stephanie, Pitari, Giovanni M., Waldman, Scott A.
• Format: Article
• Language: English
• Subjects: Adenomatous polyposis coli; Adenomatous polyposis coli protein; Administration, Oral; Animals; Apoptosis; Azoxymethane; Biosynthesis; Carcinogenesis; Cell cycle; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Colorectal Neoplasms - therapy; Cyclic GMP; Dehydrogenases; Electrolytes; Enterocytes; Enterotoxins; Glycolysis; Guanosine; Guanylate cyclase; Guanylate Cyclase - antagonists & inhibitors; Homeostasis; Hormone Replacement Therapy; Humans; Hyperplasia; Intestine; Kinases; Ligands; Metabolism; Mice; Mitochondrial DNA; Oxidative phosphorylation; Paracrine Communication; paracrine deficiency syndrome; Paracrine signalling; Peptides; Phosphorylation; Physiology; Polyposis coli; Precancerous Conditions - enzymology; Precancerous Conditions - pathology; Proteins; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide - antagonists & inhibitors; Signal Transduction; Small intestine; Stem cells; Syndrome; Tumor suppressor genes; Tumor Suppressor Proteins - metabolism; Tumorigenesis
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/j.1752-8062.2008.00040.x

The most commonly lost gene products in colorectal carcinogenesis include the paracrine hormones guanylin and uroguanylin, the endogenous ligands for guanylyl cyclase C (GCC), the intestinal receptor for diarrheagenic bacterial enterotoxins. Recently, GCC‐cyclic guanosine monophosphate (GMP) signaling has emerged as a principal regulator of proliferation, genetic integrity, and metabolic programming in normal human enterocytes and colon cancer cells. Elimination of GCC in mice produced hyperplasia of the proliferating compartment associated with increases in the rapidly cycling progenitor cells and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in the colons of mice carrying mutations in adenomatous polyposis coli gene Apc (ApcMin/+) or exposed to the carcinogen azoxymethane, elimination of GCC increased tumor initiation and promotion by disrupting genomic integrity and releasing cell cycle restriction. These previously unrecognized roles for GCC as a fundamental regulator of intestinal homeostasis and as an intestinal tumor suppressor suggest that receptor dysregulation reflecting paracrine hormone insuffciency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform overexpression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for a targeted prevention and therapy of colorectal cancer.