Tuma, Rabiya S. PHD
It has been known that inflammation increases the risk for colorectal cancer, but a mechanistic explanation has been lacking. Until now.
A study published online ahead of print in Nature Medicine (doi:10.1038/nm.2608) showed that a single inflammatory signal, prostaglandin E2 (PGE2), triggers DNA methylation, thereby shutting off tumor suppressor and DNA repair genes in colon cancer models.
The lead author, Raymond Dubois, MD, PhD, Provost and Executive Vice President at the University of Texas MD Anderson Cancer Center, said he thinks this is the first concrete mechanistic explanation for the link between inflammation and cancer: “Everybody thought inflammation created an environment that led to the expression of growth factors and cytokines, and people hypothesized that that was stimulating the growth of the tumor. But I think it is a lot more sophisticated than that,” he said.
“And I think [epigenetics] is an emerging theme that you'll hear more and more moving forward. I've heard from my colleagues that they are finding some really interesting connections between inflammation and these epigenetic changes in the expression of certain genes.”
In addition to seeing the effect on colon cancer cells in culture, the Houston team saw that PGE2 increased expression of DNA methylases and increased the rate of intestinal tumor growth in the ApcMin/+ mouse model of colon cancer.
Most remarkably though, the team saw that they could reverse the effects of PGE2 by treating the animals with celecoxib or 5-aza-2'-deoxycytidine (Aza). And combining celecoxib and Aza reduced adenoma growth more than either agent alone.
The group is already working to get a protocol approved to test the combination in late-stage colon cancer patients. As for concerns about potential side effects of the demethylating agent, Dubois points to the low incidence of adverse events in the lung cancer trial led by Steve Baylin, MD, at Johns Hopkins University School of Medicine as evidence that the drug is likely to be well-tolerated at low doses.
As exciting as these immediate results are though, Dubois notes that they represent only a minor fragment of what is actually going on in the tumor and tumor microenvironment. “We took just one mediator of inflammation, prostaglandin, and looked at it in a number of different situations,” he said. “But in the tumor microenvironment, it is very complicated. We have all the chemokines, cytokines, immune cells that are present, that have certain activities and functions. So it is a much more complicated set of factors that are acting on the transformed epithelial cell.”
In the meantime though, the new data provide new targets for therapeutic testing and new avenues for research.
© 2012 Lippincott Williams & Wilkins, Inc.