A Publication of the James Buchanan Brady
Urological Institute Johns Hopkins Medical Institutions
Volume V, Winter 2000
Evolution and Prostate Cancer
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.
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
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
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
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."
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
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.
The Western Dilemma
What is it about Western countries that makes our men so susceptible to prostate cancer, and our women so prone
to developing breast cancer? Why, as Don Coffey puts it, do those two cancers seem to go "hand in hand" -- with
countries having roughly the same high or low levels of both? And why, in comparison, are those diseases so rare
in Asian and some middle Eastern countries? What are they doing right, and what are we doing wrong? Are
Americans and Europeans -- whose rate of prostate cancer is 10 times higher than that of many Asian countries --
eating foods that cause these cancers? Or does the Asian diet somehow protect the prostate and breast against
them? Are we dealing with sins of commission or omission?
At autopsy, "incidental" prostate cancer -- small clusters of the earliest stages of prostate cancer, in an apparently
latent form that resides in millions of men -- is found in as many as half of men of every race and culture in the world.
This means that whatever causes prostate cancer in the first place -- the initiating factors or events -- happens
worldwide. The crucial difference is what happens next--whatever promotes these small cancers to grow and
become potentially lethal. In the United States, for example, those cells seem to progress into cancer that needs to
be treated in between 10 percent and 20 percent of men as they age. In AMP cancer-progression process seems
to be arrested. The cancer stays put, stays benign, never poses a problem.
Unless Asians change their lifestyle. It is well known that Asian men who migrate to the West, over time, assume the
prostate cancer risk of their new home country. So when Japanese men, people at low risk of developing prostate
cancer, move to Hawaii or California, their rate escalates over time -- to the level of an American man's. It is no longer
a question of whether diet plays a vital role in the development of prostate cancer. The question now becomes how?
More specifically, which foods are good -- or bad -- for the prostate? And is it possible, through diet, to change or delay
the onset or progression of cancer?
Asia, the cancer-progression process seems to be arrested. The
cancer stays put, stays benign, never poses a problem.
The key, scientists believe, is not the fact that cancer happens in the first place; the initiation of cancer seems to be
pretty much the same in men everywhere. It's the promotion and progression of it -- the factors, whatever they are,
that cause cancer to grow. And the factors, whatever they are -- and Hopkins scientists are hot on the trail of
identifying these -- that seem to stop cancer in its tracks.