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.