Diarrhea or colorectal cancer: Can bacterial toxins serve as a treatment for colon cancer?

Colorectal cancer exhibits a low incidence in under-developed countries even though it is the third most common neoplasm worldwide and the second most common in the U.S. (1, 2). This geographical imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. Although the epidemiology of colon cancer remains poorly understood, there is clearly an unexplained inverse relationship between the incidence of colorectal cancer and enterotoxigenic Escherichia coli (ETEC) infections (3, 4). Drawing from these observations, Pitari et al. (5) introduced an interesting hypothesis that specific peptides (STa) elaborated from ETEC may prevent the hyperproliferative and neoplastic development of intestinal epithelial cells that are associated with initiation and progression of colorectal cancer. Although a direct causal relationship between STa-mediated infectious diarrhea and low cancer rates in under-developed countries has not been proven, the authors provide convincing evidence of the presence of a novel intracellular signaling pathway initiated by STa that prevents proliferation of colon cancer cells.

Mechanistically, STa binds to guanylyl cyclase-C (GC-C) receptors specifically expressed in intestinal cells (6). Ligand binding to GC-C activates the intracellular synthesis of the second messenger, cGMP. STa hyperactivates this signaling receptor, causing large increases of intracellular cGMP ([cGMP]_int) levels (7). Despite this strong negative selective pressure of STa-mediated infection and diarrhea, GC-C and its signaling pathway have been evolutionarily conserved in a wide variety of animal species, suggesting that it must play a role in an important aspect of intestinal physiology. In this way, STa peptides represent molecular mimicry wherein enterotoxigenic bacteria have evolved a strategy for its transmission that exploits normal intestinal physiology (8, 9). Indeed, STa peptides are structurally and functionally homologous to the endogenous peptides guanylin and uroguanylin, which mediate autocrine/paracrine control of intestinal fluid and electrolyte homeostasis (9).

Recently, a new …