Cancer, even Alzheimer’s, may begin with body’s first defense
By
Rob Stein
THE
WASHINGTON POST
WASHINGTON, Feb. 16 —
Medical researchers are becoming increasingly convinced that the most
primitive part of the immune system, usually the body’s first defense
against infection and injury, may play a crucial role in some of the
most devastating afflictions of modern humans, including heart disease,
cancer, diabetes and possibly Alzheimer’s.
ACCORDING TO a theory that has
been steadily gaining ground in recent years, the immune system reaction
commonly known as inflammation has a troublesome tendency to go awry. While
inflammation’s familiar manifestations, such as the redness of an infected
cut or a raw sore throat, are unpleasant, the reaction is crucial to
survival. It unleashes powerful immune cells, enzymes and other chemicals to
fend off viruses, bacteria and other invaders, and to coax wounds to heal.
But inflammation can misfire, or fire far too long, and evidence has
been mounting that this “inflammation theory” of disease may cut across what
are usually unrelated fields of medicine.
“It’s hard now to think of a medical specialty that doesn’t concern
itself in part with the study of inflammation,” said Carl Nathan, chairman
of the department of microbiology and immunology at the Weill Medical
College of Cornell University in New York. “There’s no part of the body
that’s off limits to the inflammatory response. It can go anywhere — lung,
heart, blood vessels, brain, wherever.”
Last month, the
American Heart Association and the Centers for Disease Control and
Prevention recommended that doctors consider using a test that measures
inflammation when trying to decide how to treat patients at risk for
cardiovascular disease.
EXPLAINING ILLNESSES
In addition to potentially leading to a new generation of treatments
for cancer, heart disease and other ailments, the inflammation theory may
help explain why such ills seem to plague modern life.
“Hundreds of millions of years ago, the primary causes of death were
infection and starvation. And so the human genome selected for a gene pool
with an active immune system ... because that way you’d have a better chance
of surviving,” said Ridker at Boston’s Brigham and Women’s Hospital.
“Fast forward hundreds of thousands of years, and suddenly we’re in
an environment where infection is not a major threat and food is not scarce.
The same genes ... are now a root cause of the epidemics of diabetes and
heart disease.”
STILL A THEORY
The strength of the evidence supporting the theory varies depending
on the disease, and researchers caution it could still turn out that
inflammation plays less of a role than the surge of interest would suggest.
But the case is already very strong for heart disease, strong and getting
stronger for many cancers, and much more mixed but still tantalizing for
illnesses such as Alzheimer’s.
While it’s clear that inflammation is part of the picture in all
these diseases, the trigger for it remains unclear. For heart disease, the
spark may be bad cholesterol in the blood or possibly some
yet-to-be-identified infection inside artery walls. In cancer, it could be
chemical carcinogens such as cigarette smoke, or DNA-damaging compounds
called free radicals, or maybe viruses, bacteria or other microbes. In
diabetes, part of the problem could be chemical signals sent out by fat
cells, some of which are identical to those produced during inflammation.
“I think the first thing we have is an epidemic of unhealthy
lifestyle,” said Peter Libby, a professor of medicine at Harvard Medical
School in Boston. “And the way in which the lifestyle is wreaking its havoc
is through inflammation.”
FIRST DEFENSE
Inflammation is part of the earliest defensive system that organisms
evolved. It is what causes redness and itchiness where a mosquito bites;
heat, pain and swelling when a bowling ball lands on a foot; and sneezing,
stuffiness and aches when cold viruses invade. Aspirin, ibuprofen,
antihistamines and ice packs alleviate the nasty effects of inflammation,
but without it our bodies would be defenseless.
White blood cells, the immune system’s scouts, are constantly
patrolling, searching for anything dangerous — a virus, a bacterium, an
injury. When they detect something, they rush to the site to attack the
threat, and immediately summon help by spewing chemical signals that
urgently recruit other, more specialized cells. These cellular SWAT teams
can ooze enzymes potent enough to liquefy tissue and bone if necessary to
stem a microbial invasion.
“The innate immune cells are the shock troops of immunity designed to
respond very quickly,” said Gary S. Firestein, chief of rheumatology,
allergy and immunology at the University of California at San Diego.
‘This
is a system that has to make a decision in a very short period of time. So
you can imagine that sometimes it fires by itself, or sometimes it fires off
correctly but doesn’t slam shut properly.’
—
CARL NATHAN
Weill
Medical College, Cornell University
But scientists
have long known that the inflammatory response can boomerang. Inflammation
run amok is what causes autoimmune diseases such as rheumatoid arthritis,
multiple sclerosis and Crohn’s disease, which occur when the immune system
mistakenly attacks the joints, nerves or digestive system for reasons that
remain a mystery.
“It’s a hair-trigger kind of design,” said Nathan, who edited a
special section on inflammation published recently in the journal Nature.
“This is a system that has to make a decision in a very short period of
time. So you can imagine that sometimes it fires by itself, or sometimes it
fires off correctly but doesn’t slam shut properly.”
The idea that inflammation may be involved in other diseases began to
gain credence with the realization that stomach ulcers were caused not by
stress, worry or spicy food, but by an inflammation triggered by a bacterial
infection. Soon, evidence began to accumulate that inflammation was
important in far more than just ulcers.
“If you have a million people engineered for this bear-trap kind of
response and put them in a box called life and shake them up and down once
in a while, the bear trap will spring when it shouldn’t,” Nathan said.
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The standard theory of cardiovascular disease says cholesterol in the
blood accumulates on artery walls, like a pipe getting clogged with gunk.
Eventually the passageway gets blocked, usually by a clot, cutting off blood
to the heart or brain and causing a heart attack or stroke.
The new theory says that in addition to that process, the immune
system can also react to something in the artery, perhaps cholesterol in the
blood, devour it and suck it into the artery walls, creating something akin
to a pimple. Eventually, the pimple pops, prompting a clot to form, which
causes the blockage. That would explain why many people suddenly drop dead
from heart attacks even though their arteries look fine.
One of the ways aspirin may protect against hardening of the arteries
is by neutralizing substances called prostaglandins, some of the chemical
signals sent out during inflammation. A multitude of studies have shown that
people who take aspirin and other drugs with anti-inflammatory properties,
such as the statin cholesterol drugs, seem to have lower levels of
inflammation in their bodies and a lower risk of heart disease.
Ridker’s study, known as the Jupiter Trial, will involve 15,000
healthy middle-aged men and women with normal cholesterol to see if the
anti-inflammatory properties of statins reduce their risk. “This is the
first real test of the hypothesis,” Ridker said.
There have been clues for some time about a link between inflammation
and cancer. It has long been known that people who suffer from chronic
inflammation are at higher risk for cancer. For example, people with
ulcerative colitis, a chronic inflammation of the digestive tract, have a
higher rate of colorectal cancer.
Part of what inflammation does is promote the growth of cells to heal
wounds, and the growth of blood vessels to nourish the wounded area. But
evidence has been accumulating that many other forms of cancer may also
result from that process gone wild.
“Tumors when they’re developing are just proliferating cells. The
theory is that it looks much like a wound to the host. So inflammatory cells
come in and do their job. They urge the growth onward,” said Lisa Coussens,
an assistant professor in the department of pathology and the cancer
research institute at the University of California at San Francisco.
Scientists have found signs that inflammation may also interfere with
normal cell death and produce DNA-damaging free radicals, possibly
contributing to cells becoming cancerous in the first place, she said.
Tumors are often teeming with inflammatory cells and their chemical
messengers, and genes involved in inflammation are often active — telltale
signs that inflammation is playing a role.
Many studies have found that people who take anti-inflammatory drugs
have a lower risk for certain types of cancers, particularly colorectal
cancer, as well as precancerous growths. A study led by Robert Sandler of
the University of North Carolina at Chapel Hill is expected to be published
soon in the New England Journal of Medicine with promising results about the
power of aspirin to slash the risk of precancerous growths called polyps in
people who have had colon cancer.
‘There’s a tremendous amount of work going on in this field because of the
promise of the agents and the convergence of the data, which is quite
compelling.’
—
ERNEST T. HAWK
National Cancer Institute
Dozens of other
studies are underway exploring the potential of using anti-inflammatory
drugs to prevent, and possibly treat, a wide range of cancers, including
cancer of the breast, bladder, esophagus, skin, prostate and lung.
“There’s a tremendous amount of work going on in this field because
of the promise of the agents and the convergence of the data, which is quite
compelling,” said Ernest T. Hawk of the National Cancer Institute.
In Alzheimer’s, some scientists think that giving people
anti-inflammatory drugs early in life may forestall the development of that
devastating brain disease, though that remains highly speculative.
“It may turn out that using the anti-inflammatory drugs in your
fifties and sixties may have an impact on what’s happening in your seventies
and eighties,” said Bill Thies, vice president for medical and scientific
affairs at the Alzheimer’s Association. “People are talking about how you do
a trial to test that. This is a piece of science that still evolving.”
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-- Albert Einstein, letter to a friend, 1901
"I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."
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