Inflammation, DNA Damage, and Cancer
Jennifer Kay, PhD
The link between inflammation and cancer is a field of growing interest in the oncology community. Biologists have theorized that simultaneous DNA damage and cell division during inflammation could lead to cancer. To shed light on this important issue, The ASCO Post recently spoke with Jennifer Kay, PhD, a researcher at the Engelward Laboratory, Massachusetts Institute of Technology (MIT), whose work centers on DNA damage, inflammation, and other mechanisms that drive cell toxicity, mutagenesis, and ultimately cancer.
Can you tell us a bit about your current areas of investigation that pertain to cancer?
Our lab studies DNA repair both in vitro and in vivo. DNA repair is necessary for all organisms to survive, and it is also key to cancer prevention, because DNA repair prevents the genetic mutations in normal cells, which allow them to become cancerous. Our in vitro work is based largely around a technology called the CometChip assay (a commercial product that
The most effective ways to reduce one’s susceptibility to inflammatory diseases are a healthy diet and exercise.— Jennifer Kay, PhD
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members of the Engelward Laboratory co-invented), which enables high-throughput analysis of DNA damage in cells and also allows us to track the efficacy of the kinetics of DNA-repair processes. Our in vivo studies focus on how inflammation and chemical exposures lead to mutations that drive carcinogenesis. We have a novel “Recombomouse” that enables the detection of mutated cells in situ for assessing both the number of accumulated mutations in the tissue as well as clonal expansion of the mutant cells. Both de novo mutations and clonal expansion of mutant cells drive the development of cancer, and we’re looking at how inflammation and chemical exposures contribute to these processes.
MIT Study: Mechanisms of Inflammation
Can you tell us about the recent MIT study that found, among other things, that people who suffer from diseases such as colitis have a higher risk of mutations that cause cancer?
There are several reasons that certain diseases such as colitis predispose people to cancer. One is that the inflammation enhances the production of reactive chemical species that damage DNA, increasing extra mutations over time that may eventually cause cancer.
Another mechanism of inflammation that promotes cancer is cellular damage, which induces cellular proliferation to regenerate the damaged tissue. In our recent MIT study,1,2 our group showed the long-term accumulation of mutations from DNA damage occurring during proliferation, such as the DNA damage of inflammation overlapping with a proliferative phase of inflammation. The number of mutations increased synergistically over the number of mutations that would have been caused by DNA damage or proliferation alone.
Factors That Promote Inflammation
What is the root cause of inflammation-induced DNA damage, and are certain populations more prone to the inflammatory process?
Inflammation results in DNA damage in part because the immune system’s host-defense response includes production of reactive oxygen and nitrogen species to attack pathogens, but these chemicals can also damage the body’s own biomolecules, including DNA. DNA base pairing is essential to preventing mutations, so alteration of DNA base chemical structures creates opportunities for mutations to arise. The reactive oxygen and nitrogen species can also cause breakdown of other biomolecules such as lipids, creating reactive intermediates that can react with DNA to form adducts. Furthermore, there’s a positive feedback loop between DNA damage and inflammation, which is usually well regulated but can become imbalanced. Chronic inflammatory diseases usually result from dysregulated inflammation, rendering those with chronic inflammation much more susceptible to mutations that can lead to cancer. Chemical and environmental exposures also impact inflammation. Smoking is one of the most salient examples, but lifestyle aspects such as diet can also promote inflammation.
Some populations are more at risk for inflammation because there are genetic predispositions to certain inflammatory diseases, such as inflammatory bowel disease.
Markers of Inflammation
Do we have identifiable markers that indicate an inflammatory process is underway?
Yes, there are many markers for inflammation. For instance, inflammation increases the level of certain cytokines, which can be detected with blood work. Inflammation in different tissue samples can also be detected by more tissue-specific biomarkers. Unfortunately, the clinical symptoms of inflammation are often nonspecific or undetectable, making a diagnosis potentially difficult. So while inflammation is detectable, it is not always identified properly.
Have we identified strategies on the prevention side to possibly stall the inflammatory process?
The most effective ways to reduce one’s susceptibility to inflammatory diseases are a healthy diet and exercise. But there’s also extensive research on the anti-inflammatory effects of probiotic bacteria and antioxidants, such as green tea. There is
Inflammation is a tricky biologic process, and it can be unclear whether it is a cause or a symptom of a disease.— Jennifer Kay, PhD
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strong evidence that antioxidants can mitigate inflammation, but there’s also the possibility of consuming too many antioxidant supplements, which can damage organs such as the liver. Extensive studies, including work in the Erdman Laboratory here at MIT, show that probiotics are also effective mitigators of inflammation.
Can you share any closing thoughts on inflammation as a factor in disease?
Inflammation is a tricky biologic process, and it can be unclear whether it is a cause or a symptom of a disease. Aside from genetic predisposition and environmental exposures, we still don’t fully understand how inflammation becomes dysregulated to produce chronic diseases in otherwise healthy people.
In terms of cancer, inflammation is a major topic of interest because tumors maintain an inflammatory microenvironment around themselves to help promote their own growth. It remains to be seen how and when this microenvironment is officially generated. Other work at MIT indicates that by decreasing the toxicity of DNA-damaging chemotherapy with novel drug combinations, it may be possible to make cancer chemotherapy more effective by suppressing tumor inflammation and evolution. There’s a lot of exciting work ahead. ■
DISCLOSURE: Dr. Kay reported no conflicts of interest.
1. Kiraly O, et al: DNA glycosylase activity and cell proliferation arekey factors in modulating homologous recombination in vivo. Carcinogenesis 35:2495-2502, 2014.
2. Kiraly O, et al: Inflammation-induced cell proliferation potentiates DNA damage-induded mutations in vivo. PLoS Genet 11:e1004901, 2015.