A Closer Look at Chronic Inflammation and Prostate Cancer                                                                

There is a fine line between perfection and overkill. Take the body's immune system, for instance: "It can be quite powerful in mounting a defense against foreign organisms like viruses and bacteria," says oncologist Srinivasan Yegnasubramanian, M.D., Ph.D., The R. Christian B. Evensen Scholar. "However, it is now well recognized that the immune system can also damage our own tissues, causing a sort of collateral damage while it wards off threats to the body." This collateral damage can even last for years, he adds. Under the microscope, this damage often shows up as chronic inflammation near the damaged tissue.

Increasingly, scientists are finding this type of chronic inflammation in the prostate – particularly, in the prostates of men who eat the "Western" diet, heavy in fat and light on fruits and vegetables. Scientists at Hopkins and elsewhere have found a strong link between this inflammation and the development and progression of prostate cancer. "This inflammation has been linked to many factors, including infections in the prostate, the diet, hormonal factors, and tissue damage from trauma and urine reflux," says Yegnasubramanian. "However, despite this mounting evidence, it is still unclear whether this inflammation in the prostate is actually causing prostate cancer or not. And, if it is causing prostate cancer, what is happening on the molecular level?"

Yegnasubramanian is working to find out, with support from the Patrick C. Walsh Prostate Cancer Research Fund. "One reason that we don't understand the underlying molecular basis has been that we don't have good models that can examine the complex interplay between the immune system and prostate function and disease," he notes. But now, Yegnasubramanian and colleagues Angelo De Marzo, M.D., Ph.D., and University of Maryland Baltimore County scientist Charles Bieberich, Ph.D., have developed and started to characterize a cutting- edge, genetically engineered, new model system in mice that can closely mimic the particular inflammation seen in the human prostate. "In this model system, we can turn the propensity for chronic inflammation on and off, and examine the effects of prolonged, acute, and episodic inflammatory stress on the prostate."

With this new model system, Yegnasubramanian and his collaborators De Marzo and Bieberich hope to learn whether chronic inflammation can "directly lead to formation of prostate cancer after prolonged or recurrent stress." The scientists also will examine whether this is more likely in mice that – just like some men – have a predisposition to developing early stages of prostate cancer. And what about after cancer develops? Does chronic inflammation make it advance more quickly? Does it make cancer more likely to metastasize? Yegnasubramanian suspects that it might, by causing minuscule changes at the most fundamental level. "Based on compelling data from our lab, we hypothesize that inflammation may cause cancer formation and progression through molecular damage to the machinery that helps to interpret genetic instructions – the so-called epigenetic machinery."

This type of chronic inflammation
is increasingly common in the
prostates of men who eat the
"Western" diet, heavy in fat and
light on fruits and vegetables.

In groundbreaking research, by harnessing the latest innovations in whole-genome analysis, Yegnasubramanian and colleagues will be able to study the alterations in the epigenome that are caused by inflammation. "These studies will allow us to develop a better understanding of how inflammation can lead to the formation and progression of prostate cancer." They also, he hopes, "will ultimately allow us to develop rational approaches for treating and even preventing prostate cancer."

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