Angelo De Marzo and Don Coffey:



Their revolutionary research has resulted in a new way of thinking about how prostate cancer develops. They may also have found an extremely early warning sign of cancer -- cell changes that may be reversible.





Scientist Don Coffey, Ph.D., has taken a 4-million-year detour in his search to explain prostate cancer and learned that in the very big scheme of things, prostate cancer is an illness of fairly recent evolution. Like heart disease, it is an apparent casualty of the sedentary Western lifestyle and its notoriously unhealthy diet -- rich in animal fat, processed fare, fast food an other "junk," and poor in fresh vegetable and fruits.

In other words, it's the dark side of progress.

As resilient as we are, as remarkably adaptable as the human body is, there are some forces -- the cheesesteak, for instance -- that nature never equipped us to handle. How ironic that we, who have learned to defy gravity, can be brought down, incrementally, by years of supersized bacon burgers and meat-lover's pizzas. Today's man is far more likely to spend hours hunting for web sites or TV channels than foraging for food, his fingertips more likely stained by Cheetos than by the juices of nuts and berries. We did not evolve and develop to eat this way, says Coffey, and he can prove it. Furthermore, he and colleagues Angelo De Marzo, M.D., Ph.D., and William G. Nelson, M.D., Ph.D., are discovering, on a microscopic level, how this drama of evolution plays out in the most primitive, fundamental cells in the prostate. This groundbreaking research may one day lead to the earliest marker yet for prostate cancer -- and may help scientists prevent or even reverse cell damage before it's too late.





There are some forces -- the cheesesteak, for instance -- that nature never equipped us to handle.





An Evolutionary Wrong Turn





The saga of human evolution is also a story of two male glands, both of which produce fluid that makes up semen. One gland, the prostate, is prone to cancer. The other, the seminal vesicle, is remarkably free of it. Only mammals have prostates. By definition, only mammals have breasts, as well. Breasts and prostates seem to have evolved on parallel tracks, says Coffey: When some animals evolved into mammals -- in other words, "when the female developed the breast, and fed her children by breast milk, that's when the prostate appeared in the male." Today, breast cancer and prostate cancer seem to be two sides of the same coin, as well: Countries with high rates of breast cancer tend to have a lot of prostate cancer; countries with low rates of prostate cancer have relatively few case of breast cancer. When people migrate from areas with little breast or prostate cancer to places with high rates, their own odds increase with time (see "The Westen Dilemma". In nature, animals that are carnivores -- meat-eaters like lions -- don't have seminal vesicles. The only animals that have both prostates and seminal vesicles are herbivores--veggie-eating animals like bulls, apes, and elephants. We are the huge glaring exception to this rule: Men have seminal vesicles, too. In other words, man, a meat-lover has the makeup of an animal that should be a vegetarian. The fact that men eat meat seem to be a mistake that nature never accounted for. How can this be? In exploring this question, Coffey looked a few rungs further down the evolutionary ladder and found the pigmy chimp, called the bonobo, "the closest ape to which we at distant relative." Bonobos and humans have many things in common. Diet is not one of them: Bonobos are--as humans probably were, very long ago -- vegetarians. They don't get prostate cancer. "Most apes only eat fruits and vegetables and greens," says Coffey. "When we climbed down out of the trees, we became hunter-gatherers -- but it's only recently that humans started eating and processing meat in a big way. In fact, out of the 4 million years since we split off from the great primates, it's only in the last 600,000 years that we even cooked. All that time, we were eating whatever we could scavenge and catch." About 12,000 years ago, humans took the next big step and started producing their own food. "This was a major change in diet and lifestyle: We changed from the way we had evolved, and started eating more processed meat. We quit running after animals, started herding them, and then started breeding them in captivity. We became sedentary. We quit eating a great variety of fresh vegetables and greens from 3,000 types down to about 20. We started smoking our meat, salting it, putting nitrates on it. Now we get everything from the store, nothing from a farm. We call it fresh, but it's not fresh, especially our meat," which most of us prefer well-done, not raw. "Everything is cooked." For decades, the American Cancer Society and National Cancer Institute have urged Americans to lower their cancer risk by changing their diet: "Cut down the animal fats, cut down the dairy products," says Coffey. "We were not big dairy people until 3,000 years ago; now, we put cheese on everything that moves. A few apes eat meat, but no ape ever cooked or put cheese on anything. We need more fiber, more fresh fruits and vegetables, more aerobic exercise. All of our experience in cancer prevention is telling us to return to the way we evolved."





This groundbreaking research may one day lead to the earliest marker yet for prostate cancer -- and may help scientists prevent or even reverse cell damage before it's too late.





If breast and prostate cancer, as Coffey believes, are indeed developing from our evolutionary wrong turn, then how to prove it? Coffey pored over zoo records from around the world, and found that" no animal in the zoo as it ages dies from prostate cancer or breast cancer. There are only three cases of cats dying of prostate cancer. Horses do not die of prostate cancer, bulls do not die of it, only a very few primates have ever died of it." Yet one out of every 10 American men gets prostate cancer. And the only animal to develop clinical prostate cancer with any significant incidence is the dog -- the pet that eats most from our table.





An Exciting Now Finding: The Roots of Cancer In the Prostate



But how, exactly, does diet cause changes that lead to cancer? Coffey put this next question directly to the prostate, with stunning early results: In breaking research, Coffey and colleagues John Isaacs, Angelo De Marzo, Alan Meeker, and Bill Nelson have combined their efforts to implicate what appears to be a tiny garden of good and evil, tucked away deep in the prostate. A heretofore hidden nursery of thousands of "stem" cells seeds that divide and grow into mature prostate cells that accumulate. "These stem cells can make your prostate grow or shrink," Coffey explains. "When you take away androgens (male hormones that feed and stimulate the prostate), the mature cells shrink, and when you give back androgens, those seeds of stem cells grow them back up." Normally, these stem cells divide and then don't divide; they turn on and off like a light bulb. When they divide, they give birth to children -- tall stalks called mature epithelial cells. These epithelial cells, in turn, become little factories that produce PSA and the fluids that make up the prostate's contribution to semen. When all is well and good within the prostate, these fragile stem cells are cherished, sheltered and safeguarded-- wrapped in velvet, as it were, cushioned by protective enzymes such as glutathione-S transferase p (see Prostate Cancer Diet) that protect against anything that might damage their DNA. However: "At the very earliest stages of prostate cancer, some of the important properties possessed only by the stem cells -- most importantly, the ability to divide and grow indefinitely shift up into the mature epithelial cells, says De Marzo. Ordinarily, "this would be fine, because the epithelial cells can turn on their glutathione-S transferase p and stay protected." But Bill Nelson has discovered that sometimes -- in men who develop cancer -- a destructive force knocks out the "good guy": It obliterates glutathione-S transferase p. Without their enzyme bodyguard, the dividing epithelial cells are suddenly vulnerable. "They've lost their ability to protect themselves, and therefore they accumulate DNA damage," says Coffey. The epithelial cells start replicating like crazy, churning out many different species of damaged cells -- many of them cancerous. "These cells are highly resistant to therapy, because there's such a variation." The errant process "creates biological diversity in your prostate at the wrong time -- it turns on evolution at the wrong time," says Coffey. "Whereas down in the stem cells, sometimes they go out of control, but they don't have this unprotected replication. When they build up, they just make more normal cells -- this is called BPH, benign prostatic hyperplasia. But it does not go on to cancer." So this, Coffey and De Marzo believe, may be the equation -- or at least a good part of it -- for prostate cancer: The absence of glutathione-S transferase p, plus wild replication in the epithelial cells. "As long as replication was in the stem cells, where the protection was, they were okay," says Coffey. "But in cancer, these stem cells disappear, and it's the epithelia] cells that are dividing -- and they're the ones that kill you." This revolutionary research -- by Coffey and De Marzo, with Bill Nelson's work on glutathione-S transferase p, and Coffey and John Isaacs' stem cell models -- has resulted in a new way of thinking about and explaining how prostate cancer and BPH develop, and how they're different. But remember the destructive, DNA-damaging force unleashed in the garden? What allows it in, weakening the body's defenses, damaging the "good" cells when the enzyme glutathione-S transferase p is turned down? The Brady researchers believe the answer may be in the diet. De Marzo and Coffey have discovered a subtle change in prostate tissue, an inflammation (on a much smaller scale, and much different from the overall inflammation that characterizes clinical prostatitis). "For some reason, there's a little auto-immune reaction. And this prostate inflammation makes highly reactive oxygen species -- free radicals -- which attack the DNA like crazy."



"These cells are highly resistant to therapy, because there's such a variation." The errant process "creates biological diversity in your prostate at the wrong time -- it turns on evolution at the wrong time."



Glutathione-S transferase p protects against these free radicals. So does selenium--a mineral found in the soil, present in some vegetables, most over-the counter vitamins, and available as a dietary supplement. So does soy. "We did an experiment with rats," says Coffey, "and found that when we put them on a soy-free diet, they got lots of prostate inflammation. We put them on a moderate soy diet, they got very little. When we put rats on a high-soy diet, they got none. So diet can control inflammation of the prostate. Diet can also turn those protective enzymes on and off." Most recently, De Marzo has identified a new lesion in the prostate--a very early area of cell damage, which he calls proliferative inflammatory atrophy, or PIA. This precedes PIN (prostatic intraepithelial neoplasia -- abnormal cells, often found in a needle biopsy, which are strongly linked to prostate cancer). So PIA -- the discovery is new, and Brady scientists have just begun to investigate it -- may, one day, be considered pre-precancerous. The PIA cells appear to be shut down, or atrophied, and they're surrounded with inflammation. "But they're highly active for DNA synthesis," says Coffey. "In other words, they're replicating wildly." And in this volatile area, Nelson and De Marzo have observed that levels of glutathione-S transferase pfluctuate heavily. If what the scientists are witnessing is a microscopic Alamo -- the enzyme's last stand, in effect -- then "that would be the death knell for what starts the cancer process," says Coffey. PIA might also become an extremely early warning sign of prostate cancer, and if it is indeed reversible, perhaps -- one day, if caught in its earliest stages -- cancer may be, as well.

