Guanylyl cyclase C (GC-C) regulates the dynamics of the proliferating compartment of intestinal crypts

Abstract

Background GC-C, the receptor for bacterial heat-stable enterotoxins (STs) and the endogenous ligands guanylin and uroguanylin, regulates volume homeostasis in intestine. Beyond fluid balance, GC-C inhibits colon cancer cell proliferation, although a role of this receptor in regulating normal enterocyte dynamics remains undefined. Methods Regulation of proliferation was examined in vitro and ex vivo employing NCM460 human colon crypt cells and human colonic mucosa cells from patients, respectively. Regulation of enterocyte dynamics in vivo was examined employing null mice for GC-C expression (GC-C−/−). Results Activation of GC-C by ST induced cGMP accumulation and reduced cell cycle progression in NCM460 cells. A cell-permeant analog of cGMP, 8-br-cGMP, mimicked the effect of ST and induced a transient cell cycle delay at the G1/S transition. GC-C−/− mice exhibit increased length of the crypt-villus axis in small intestine and the crypt-lumen axis in colon. Elongation of this axis reflected expansion of the crypt proliferating compartment, populated by more rapidly cycling and migrating progenitor cells. Moreover, ST and 8-br-cGMP inhibited the proliferation of normal human colonic mucosa cells from patients. Conclusions As expression of guanylin or uroguanylin is frequently lost in colorectal tumors, the expansion of the crypt proliferating compartment in GC-C−/− mice suggests a role for this receptor as a tumor suppressor contributing to intestinal carcinogenesis. Clinical Pharmacology & Therapeutics (2005) 77, P22–P22; doi: 10.1016/j.clpt.2004.11.084