GCC signaling in colorectal cancer: Is colorectal cancer a paracrine deficiency syndrome?
Guanylyl cyclase C (GCC) is the receptor expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin that coordinate mucosal homeostasis and its silencing contributes to intestinal transformation. It orchestrates proliferative and metabolic circuits by limiting the cell cycle and programming metabolic transitions central to regeneration along the crypt-villus axis. Mice deficient in GCC are more susceptible to colon cancer induced by germline mutations or carcinogens. Moreover, guanylin and uroguanylin are the most commonly lost gene products in colon cancer. The role of GCC as a tumor suppressor and the universal loss of its hormones in transformation suggest a paradigm in which colorectal cancer is a disease of paracrine hormone insufficiency. Indeed, GCC signaling reverses the tumorigenic phenotype of human colon cancer cells by regulating proliferation and metabolism. These data suggest a pathophysiological hypothesis in which GCC is a tumor suppressor coordinating proliferative homeostasis whose silencing through hormone loss initiates transformation. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral hormone replacement therapy employing GCC ligands.
Li
P
P
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Lin
J E
JE
Marszlowicz
G P
GP
Valentino
M A
MA
Chang
C
C
Schulz
S
S
Pitari
G M
GM
Waldman
Scott A
SA
D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D016503:Drug Delivery Systems; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D018000:Receptors, Peptide; C072685:guanylin; C084362:uroguanylin; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled