For more than 100 years, researchers have sought links between inflammation and cancer. Now, a team of scientists studying gastrointestinal cancer in mice presents powerful evidence of a molecular connection between those conditions.
In two experiments, researchers at the University of California, San Diego showed that deactivating a protein called I-kappa-B kinase beta (IKK-beta) inside cells stops cancer progression in its tracks.
IKK-beta normally plays a role in healing. During infection or injury, immune system molecules activate IKK-beta. Once stimulated, this protein keeps cells alive and growing, despite the insult. IKK-beta also promotes inflammation in damaged tissues.
These effects could be a double-edged sword in the presence of carcinogens, says molecular biologist Michael Karin. Before the experiments, he speculated that, by preventing programmed cell death and encouraging inflammation, IKK-beta also promotes the emergence and growth of tumors.
"This hypothesis was a no-brainer, but it's hard to prove it," Karin says.
To show the protein's role in tumor development, Karin and his team genetically engineered mice to lack the gene for IKK-beta in specific parts of their bodies. In the first experiment, the researchers deleted the gene in cells lining the intestines of 12 mice. They injected these mice, as well as 12 normal mice, with an irritant to injure the intestines and provoke an immune response. Simultaneously, the mice received a chemical that typically triggers tumor growth in the gastrointestinal tract.
After 12 weeks, all 24 mice had intestinal tumors, but the researchers saw a dramatic difference between the two groups, says Karin. The mice without intestinal IKK-beta had one-fourth as many tumors as did the normal mice, the researchers report in the Aug. 6 Cell. Without the cell-preserving actions of IKK-beta, precancerous cells died before tumors were even initiated, Karin speculates.
In the second experiment, researchers deleted IKK-beta from bone marrow cells. This thwarted white blood cells, which arise from the marrow cells, from manufacturing inflammatory proteins that could assist tumor growth. After receiving the irritant and cancer-triggering chemical, 12 mice lacking IKK-beta in the marrow cells showed only half as many tumors as did 12 normal mice. Also, the tumors were much smaller in the mice lacking IKK-beta.
In this case, the body's fight against tumors occurred by a different mechanism than in the first experiment, says Karin. White blood cells missing IKK-beta don't rush to a tumor, which therefore gets fewer nutrients and grows more slowly.
IKK-beta thus assists tumor growth in different ways in different types of cells, says Karin. One way subverts the programmed cell death that would otherwise prevent tumor formation, whereas the other way promotes tumor development through inflammation.
"I don't believe I have ever seen such a clear relationship between inflammation and cancer as I did in this case," says Mina Bissell, a cancer researcher at Lawrence Berkeley National Laboratory in Berkeley, Calif. "It's really a lovely piece of work."
Many cancers of the digestive tract are associated with bacterial infections, such as Helicobacter pylori in the stomach, and injury, such as that from inflammatory bowel disease in the colon. In these instances, many scientists agree that the immune system and inflammation play a role. It's not clear, however, that inflammation participates in other types of cancer, says Karin.
Drug companies are already working to develop IKK-beta inhibitors to cure inflammatory diseases such as rheumatoid arthritis, says Karin, "but we think [they] will be much more useful in cancer."
Mina J. Bissell
Life Sciences Division
Lawrence Berkeley National Laboratory
One Cyclotron Road
Berkeley, CA 94720
Department of Pharmacology
University of California, San Diego
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Department of Anatomy
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University of California, San Francisco
San Francisco, CA 94143