The incidence of colorectal cancer — a major cause of mortality in industrialized nations — is lowest in developing countries, where high levels of enterotoxigenic Escherichia coli (ETEC) infection are seen. Whilst it has been thought that there is a link between cancer and ETEC, the mechanisms that underlie this inverse relationship have been poorly understood. In the February 10 Proceedings of the National Academy of Sciences, G. M. Pitari and colleagues at the Thomas Jefferson University, Philadelphia, USA, show that a bacterial heat-stable enterotoxin suppresses colon cancer cell proliferation by a guanylyl cyclase C-mediated (GC-C) signaling cascade (PNAS, DOI:10.1073/pnas.0434905100, February 10, 2003).

Pitari et al. examined the in vitro DNA synthesis and proliferation of colon cancer cells in the presence of heat-stable enterotoxin (ST) produced by ETEC. They observed that ST suppressed proliferation by increasing intracellular cGMP — an effect mimicked by the cell permeant analog 8-br-cGMP. In addition, they showed that both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca2⁺ influx and inhibition of DNA synthesis in colon cancer cells.

"Oral administration of GC-C ligands or downstream effectors of that pathway, such as calcium, offer a hitherto unknown approach to the primary prevention of intestinal neoplasia and/or therapy of colorectal cancer metastases," conclude the authors.