Johns Hopkins Kimmel Cancer Center scientists report that sharp rises in levels of reactive oxygen molecules, and the inflammation that results, trigger biochemical changes that silence genes in a pattern often seen in cancer cells. The researchers confirmed this gene-silencing effect in mice that develop inflammation-induced colon cancer.
The study, reported Nov. 14 in Cancer Cell, is believed to be the first to identify a specific molecular mechanism linking inflammation to cancer epigenetics. Epigenetic changes alter the usual patterns of gene expression in cells and typically cause the silencing of tumor-suppressor genes.
"Our finding could explain why epigenetic changes are found in cancer cells and one important reason inflammation is so frequently linked to cancer," says Stephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for Cancer Research and deputy director of the Johns Hopkins Kimmel Cancer Center.
In the past several years, researchers have noted that cancers linked to chronic inflammation, such as some colon tumors, appear to be enabled by early changes in patterns of DNA methylation, the addition of a molecule known as a methyl group to the "engine-starter" region of a gene known as a promoter. Methylation events reduce or completely shut down the gene's ability to make functional proteins. Cancer cells typically show abnormal patterns of DNA methylation.
How inflammation brings about these epigenetic abnormalities has not been clear, but in a study reported in 2008, scientists led by Baylin and research associate Heather M. O'Hagan found an important hint. Working on lab-grown cells, they created a model of DNA damage caused by severe inflammation and found that methylating enyzmes known as DNA methyltransferases soon appeared on the scene, as part of the cellular DNA-repair crew.
For the new study, Baylin's team exposed cells to high levels of hydrogen peroxide, a strongly reactive molecule - known as a reactive oxygen species - which is emitted by a variety of cells during episodes of inflammation. Hydrogen peroxide can damage DNA, as well as other proteins and structures within cells. Baylin's team, in experiments led by O'Hagan and graduate student Wei Wang, found that peroxide-induced damage recruited methyltransferases to damage sites. The enzymes also appeared to form large, molecular complexes with other proteins involved in epigenetic gene-silencing.
These effects did not appear when DNA was damaged by gamma or ultraviolet radiation, suggesting that they are largely a result of reactive oxygen damage induced by inflammation.
The team also saw rapid abnormal DNA methylation in several genes whose promoter regions contain dense groupings of cystine and guanine molecules known as CpG islands. Their epigenetic silencing also is known to contribute to cancer. Further studies with Johns Hopkins colleagues Cynthia Sears and Robert Casero showed that these protein interactions are seen in mice with a bacterially induced form of colon inflammation - a condition that accelerates the development of colon cancer in the animals.
Baylin and his colleagues suspect that epigenetic silencing evolved to temporarily give inflamed tissue an opportunity to repair and renew itself. However, when inflammation becomes chronic and lasts too long, Baylin says the silencing process may "become locked-in for some vulnerable genes." The loss of these genes may allow uncontrolled cell division and growth, bringing them one step closer to cancer, he says.
Chronic inflammation induced by viruses, bacteria, toxins and autoimmune processes is well known to promote common types of cancer, including colon, lung and liver cancer. "Our hope is that by understanding how inflammation brings about this abnormal epigenetic process, we might be able to use drugs to target it and thereby prevent many cancers," Baylin says.