Colorectal cancer is a paracrine deficiency syndrome amenable to oral hormone replacement therapy.

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-cGMP 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 rapidly cycling progenitor cells, and reprogrammed enterocyte metabolism, with a shift from oxidative phosphorylation to glycolysis. In addition, in colons of mice carrying mutations in Apc (Apc(Min) (/+)) 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 insufficiency is a key event during the initial stages of colorectal tumorigenesis. Together with the uniform over-expression of GCC in human tumors, these novel roles for GCC underscore the potential of oral replacement with GCC ligands for targeted prevention and therapy of colorectal cancer.