What Does Inflammation Have to Do With Cancer?
Trio Closes in on "Smoking Gun"

Multidisciplinary "Dream Team:" Nelson, De Marzo, and Isaacs, along with a laser capture microscope that was funded by the Peter Jay Sharp Foundation. With this advanced instrument, scientists can collect DNA and RNA from the nuclei of individual cancer cells, and find the genetic fingerprint for prostate cancer.


Imagine a movie about a great adventure-a bold jewel heist, a daring escape-and consider the characters. There's the demolitions expert, the safe-cracker, the code-breaker-all specialists, who tackle one facet of a job that looks to be impossible. This kind of multidisciplinary team is the Walsh Fund in a nutshell, and it's happening every day at Johns Hopkins. One of the best examples of it might be called the Brady's own "Dream Team"-a trio of investigators from different scientific backgrounds-oncologist William G. Nelson, M.D., Ph.D., molecular geneticist William B. Isaacs, Ph.D., and pathologist Angelo M. De Marzo, M.D., Ph.D.

Because prostate cancer is so very complicated, and its tapestry of origins seems so intricately woven together, the goal of pinpointing its earliest beginnings has long seemed as formidable as the mountain fortress in the movie, "The Guns of Navarone." But the questions these scientists are asking-and figuring out how to answer-are revealing unexpected cracks in the citadel. Their work so far, recently summed up in a landmark paper in the New England Journal of Medicine, has identified a new target-which may, in fact, be the "smoking gun" that causes prostate cancer.

Methylation: Silencing genes

For the last decade, Bill Nelson has been looking at what we eat, what we don't eat, and trying to figure out what we should eat. His pioneering work on the role of diet in prostate cancer has shown that oxidative damage to DNA-incremental damage accrued as carcinogens hammer away at our genes, like invaders with tiny battering rams-is a major factor responsible for the development and progression of the disease. He also discovered that the major gene that defends prostate cells against this damage, called GSTP1 (also known as GSTp)-is knocked out of commission early in the development of cancer. The gene, he learned, is "hypermethylated"-in chemical terms, it picks up an extra building block that changes its shape. This extra baggage has an effect that's akin to changing a lock, so the normal key doesn't fit it any more.

How does this fit in with what we already know about cancer and the genes? "It's an idea that's taking on new importance," says Nelson. "In addition to helping us under-stand what causes cancer, methylation is also being used to help detect it, as we identify new tumor markers." This discovery of hypermethylation changes is like finding a set of molecular fingerprints-"which means that we have something new to look for and monitor, to help us detect, diagnose, and predict the course of prostate cancer." (For more, read "Is it Cancer?" ) Scientists have long known that cancer is caused by changes in how our genes work. Tumor suppressor genes, for example, hamper a gene's ability to do its job; in contrast, oncogenes cause a gene's function to be "revved up," and result in out-of-control growth of cells.

It's chaos on a microscopic level. Some cells atrophic but growing out of control, some cancerous, some inflamed, some funny-looking, and some normal-a primordial breeding ground of cancer.


Methylation falls into a third category of genetic troublemaking, causing what scientists call "epigenetic" change. Here, the genes aren't altered; instead, they're silenced. A gene is methylated and boom-it's useless. In effect, it's put into a chemical straitjacket. Nelson has also learned that antioxidants such as vitamin E and selenium, and cruciferous vegetables such as broccoli, which protects GSTP1, can help detoxify cells by preventing oxidative damage.

Epicenter of Cancer: Inflammation?

Meanwhile, pathologist Angelo De Marzo, with the help of his mentor, Jonathan Epstein, the Rose-Lee and Keith Reinhard Professor of Urologic Pathology, has made startling findings in studies of prostate tissue. He has seen cancer cells, and nearby, the suspicious-looking cells called PIN (prostatic intraepithelial neoplasia). PIN cells aren't cancer, but they're not normal, either; the general feeling among pathologists is that they're cancer waiting to happen. And right in the thick of these cancerous and probably precancerous cells, he's seen something else-hotspots of inflammation. And sprinkled around this inflammation were areas of atrophy-cells that appeared to be dying, but actually, under closer inspection, were proliferating very rapidly. Basically, what De Marzo has identified is chaos on a microscopic level-some cells atrophic but growing out of control, some cancerous, some inflamed, some funny-looking, and some normal. A primordial breeding ground of cancer. De Marzo named this inflammation PIA, for proliferative inflammatory atrophy, and identified it as a specific precursor lesion for prostate cancer.

Could it be that inflammation, either in conjunction with other things, such as diet and heredity, or-and this is the concept that has Brady scientists buzzing-by itself, is the cause of the oxidative damage that leads to cancer? There is precedent for this idea. Inflammation is known to cause damage to cells and to DNA; unremitting, long-term inflammation is associated with many kinds of tumors. For example, chronic hepatitis causes cancer of the liver; chronic stomach inflammation, caused by a form of bacteria known as h. pylori, causes stomach cancer; reflux esophagitis, over time, can cause cancer of the esophagus.

Do Genes Hold the Answer?

The next question is, what causes this inflammation? Molecular geneticist Bill Isaacs, Ph.D., and colleagues have been asking this question in an entirely different way. They have spent the last decade studying families with hereditary prostate cancer, trying to determine how mutations in certain genes stack the deck toward cancer in some men. They have found two genes that are responsible for the development of prostate cancer in small clusters of families: One, located on chromosome 1, is RNASEL; the other, located on the short arm of chromosome 8, is called MSR1 (macrophage scavenger receptor 1). These genes have something very interesting in common-they're both involved in the body's defense against infection. When animals that lack the MSR1 gene are infected with bacteria, or animals with a defective RNASEL gene catch the herpes simplex virus, 60 percent of the animals die. And this observation, says Bill Isaacs, "raises the intriguing possibility that viral or bacterial infections might be the source of the chronic inflammation in some patients, and that this chronic inflammation might be responsible for the increased risk of prostate cancer." If it's true, he adds, "this will profoundly affect future studies of the causes of prostate cancer, and may ultimately lead to new approaches to prevent it."

"It's a very futuristic approach," says Patrick C. Walsh, M.D., "a whole new idea that we're exploring. The idea is that a decreased ability to fight infections could result in chronic inflammation, and chronic inflammation leads to tissue injury and ultimately, to oxidative damage. This, in turn, leads to mutations in DNA, and mutations lead to cancer." One of the best examples of this is that of stomach cancer, Walsh continues. "For years, everyone believed that stomach cancer was caused by dietary factors, but we now know it was caused by h. pylori, which was an unrecognized pathogen until recently. It would be fascinating to see whether there might be a similar organism that causes prostate cancer."



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