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
| 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