Blood vessels, colorectal cancer
Blood vessels, colorectal cancer

Although I usually talk about reduced immune responses in relation to tumor progression, I’ve also mentioned the possibility that chronic inflammation — excessive immune response –may enhance tumor progression as well. For example, chronic hepatitis B infection leads to about a 10-fold increase in the risk of liver cancer, probably because of the chronic inflammation associated with the virus. 1 At least one reason for the increased risk is that inflammation produces reactive oxygen and nitrogen species (RONS). RONS are toxic to microbes, but not surprisingly they’re also somewhat toxic to the host cells as well. In particular, RONS are mutagenic.

At any rate, that’s been the proposed reason for the increased risk, but this apparently hadn’t been formally tested. (It’s not a field I follow intently, so I am taking someone else’s word on that; but I don’t know of any tests.) A paper in Journal of Clinical Investigation now has looked at this specifically2, and though it’s not directly related to viral immunity the message is probably relevant in that context as well. The authors asked what happens when chronic inflammation takes place in mice that can’t efficiently repair the DNA damage that RONS induces. (These are mice that lack a particular DNA repair enzyme, alkyladenine DNA glycosylase (Aag).)

Helicobacter pylori
Helicobacter pylori

If the hypothesis is correct, then the wild-type and the mutant (repair-deficient) mice should both be okay with acute inflammation, but the mutant mice should have increased risk of cancer with chronic inflammation. Using a chemical to induce gastrointestinal inflammation, that’s pretty much what happened; there were more cases of colorectal cancer in the mutant mice that couldn’t repair RONS-induced DNA damage. 3  However,this isn’t due to a globally higher risk of tumors.  The mutant mice didn’t have any different rate of tumors in a different model of carcinogenesis (crossed to a tumor-prone strain of mice), implying that it is specifically chronic inflammation that’s the problem.

They then moved the experiment into clinical territory by infecting the mice with Helicobacter pylori, the stomach ulcer bacterium. Humans infected with H pylori have chronic inflammation of the gastrointestinal tract, of course, and they also have increased risk of gastric cancer.4 The mutant mice didn’t actually develop tumors in this experiment, but they did have much more severe gastric lesions (“histopathologic lesions that were markers of increased predisposition to, or were precursors to, gastric cancer“).

So reducing the ability to clean up after RONS doesn’t alter the normal risk of cancer, but does increase the risk when chronic inflammation is present. In an interesting conclusion, the authors suggest that it might be useful to look at variation in these DNA repair enzymes as a marker for tumor risk in several diseases:

This may be particularly important for gene-environment interactions with states of chronic inflammation or with other conditions known to increase oxidative stress such as metal storage diseases, heavy metal exposure, smoking, and chronic infection.

  1. For a review: de Visser, K.E., Eichten, A., Coussens, L.M. (2006). Paradoxical roles of the immune system during cancer development. Nature Reviews Cancer, 6(1), 24-37. DOI: 10.1038/nrc1782[]
  2. Meira, L.B., Bugni, J.M., Green, S.L., Lee, C., Pang, B., Borenshtein, D., Rickman, B.H., Rogers, A.B., Moroski-Erkul, C.A., McFaline, J.L., Schauer, D.B., Dedon, P.C., Fox, J.G., Samson, L.D. (2008). DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. Journal of Clinical Investigation DOI: 10.1172/JCI35073[]
  3. Actually, they say it’s exactly what happened, but I’m a little puzzled by their statistics; unless I’m missing it, though, there’s not enough information included in the paper for me to repeat the analysis.[]
  4. Helicobacter pylori infection and the pathogenesis of gastric cancer: A paradigm for host-bacterial interactions. D. McNamaraa and E. El-Omar. Digestive and Liver Disease (2008) 40:504-509 doi:10.1016/j.dld.2008.02.031 []