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Missing Link Ties Cancer to Chronic Infection

Major Finding Could Lead to 20% Drop in Cancers

By Daniel DeNoon
WebMD Medical News Reviewed By Brunilda Nazario, MD
on Thursday, August 05, 2004

Aug. 5, 2004 -- One of the great missing links in cancer research
isn't missing any more.



Some cancers appear to be linked to long-lasting infections. But
nobody knew why -- until now. The new findings come from the lab of
Michael Karin, PhD, at the University of California in San Diego. The
Karin team's report is the cover story in the Aug. 6 issue of Cell.


Infections provoke an immune response from the body. Part of this
response is inflammation. Inflamed tissues swell, redden, and leak
fluids full of chemical signals to the immune system. Galen, the
great Greek doctor, noticed a link between inflammation and cancer
some 2,000 years ago. Our word "tumor," in fact, comes from the Latin
word tumere, to swell.


"These findings really explain how inflammation can promote cancer.
There is no question about it," Karin tells WebMD. "And if we learn
how to decrease the effect of inflammation on cancer, we could
prevent 20% or more of all cancers."


Herman Kattlove, MD, MPH, medical editor at the American Cancer
Society, is more restrained about the findings.


"My sense is that most cancers are not related to inflammation,"
Kattlove tells WebMD. "Most cancers -- unless there is something we
don't know -- most are not related to inflammation."


But Karin stresses the observation that more than one in five cancers
worldwide is linked to long-term infections. Hepatitis viruses, he
says, don't carry any cancer-causing genes. Yet they are linked to
inflammation of the liver, which increases a person's chances of
liver cancer.


Eric Jacobs, PhD, senior epidemiologist for the American Cancer
Society in Atlanta, agrees that several kinds of cancer are linked to
infections. And there's another line of evidence, he says.


"Aspirin use, and use of aspirin-like drugs that reduce inflammation,
can reduce the risk of certain cancers," Jacobs tells WebMD. "The one
strongly established link to lower risk in aspirin users is
colorectal cancer -- and there's pretty good evidence in gastric
cancers."



The Missing Link


One cancer that nearly everybody agrees is linked to inflammation is
colitis-associated cancer. Colitis is a disease that causes long-term
inflammation of the gut.


"In humans, colitis-associated cancer accounts for 5% to 15% of all
colorectal cancer," Karin says. "People with chronic colitis have a
very, very high risk of developing colorectal cancer. Usually it is
the cancer that kills them, not the colitis."


So Karin's team looked at mice given intestine-irritating and cancer-
causing chemicals. As expected, these mice got colon cancer.


What about inflammation makes a normal cell a cancer cell? Karin
suspected it's an important chemical messenger called NF kappa B.
Normally, NF kappa B sits around in the body of a cell. But when that
cell gets a warning that an infection is under way, NF kappa B moves
to the nucleus of the cell -- the cellular control room -- where it
switches on inflammation.


That's not all NF kappa B does. It also shuts down a cell's death
program. Activation of the cell death program is a major way for the
body to get rid of cancer cells. And the key that unlocks NF kappa B
is an enzyme called IKK beta.


Using sophisticated genetic manipulation, Karin and colleagues
knocked out the IKK beta genes in the intestinal cells of their
experimental mice. Four out of five times, these mice didn't get
colon cancer.


"This shows that IKK beta affects the cancer at a very, very early
stage," Karin says. "Hopefully, it would lead to what we think would
be chemoprevention rather than chemotherapy. To get better cancer
treatments is very important. But what is even better is to prevent
the cancer at an early stage rather than treat it after it develops."


IKK beta turns out to be a very important chemical messenger for the
immune system. Drugs that kept it from working, Karin says, couldn't
be used for a long time. But they might be tolerable long enough to
prevent cancer. Several companies, he says, already are developing
IKK beta-inhibiting drugs.



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SOURCES: Greten, F.R. Cell, Aug. 6, 2004; vol 118. Michael Karin,
PhD, professor of pharmacology, University of California, San Diego.
Herman Kattlove, MD, MPH, medical editor, American Cancer Society,
Los Angeles. Eric Jacobs, PhD, senior epidemiologist, American Cancer
Society, Atlanta.