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Research Brief 118Superfund Basic Research ProgramEvidence of a Molecular Link Between Inflammation and CancerRelease Date: 10/06/2004 More than one in five cancers in the world is linked to long-term infection. Dr. Michael Karin of the University of California-San Diego SBRP leads a team of researchers that has identified the key molecular mechanism linking chronic inflammation to cancer. In a two-part study, they showed that deactivating I-kappa-β kinase beta (IKK-beta) inside cells significantly reduced the incidence of cancer. IKK beta, a proinflammatory gene, is required for activation of the protein nuclear factor kappa (NF-κB), which acts as a master switch to turn on inflammation in response to bacterial or viral infections. NF-κB keeps cells alive and growing, and promotes inflammation in damaged tissues. The researchers genetically engineered two strains of mice, one lacking IKK beta in the epithelial cells lining the intestine, the second lacking IKK beta in myeloid (bone marrow) cells. They treated three groups if mice with azoxymethane, a pro-carcinogen, and dextran sulfate sodium salt, a pro-inflammatory irritant, and observed that:
Dr. Karin and his colleagues conducted biochemical tissue and DNA analyses to identify the mechanisms leading to these trends. They determined that IKK beta acts very early in the carcinogenesis process, in different ways in the two cell types. In the epithelial cells, the carcinogen genetically transforms the cells to give rise to malignant cells. This process, however, needs assistance from NF-κB. But the mechanism by which NF-κB acts to promote tumor development differs between the two cell types. The UCSD team found that in mice lacking IKK beta in epithelial cells, incidence of cancer was decreased not through decreased inflammation, but through stimulation of apoptosis or "programmed cell death". Apoptosis functions to remove mutated or chemically transformed cells, as well as useful cells that have outlived their purpose. In mice lacking IKK beta in epithelial cells, increased apoptosis resulted in the death of many precancerous cells before tumors had a chance to progress. In myeloid cells, the researchers did not detect any impact of IKK beta deletion on the apoptosis of the chemically-transformed epithelial cells. Instead, they found that IKK beta deletion in myeloid cells decreased the expression of pro-inflammatory cytokines that are normally expressed at sites of inflammation and could assist tumor growth. This research establishes for the first time the role of myeloid cells in inflammation-associated tumor promotion in addition to their role in tumor progression and invasiveness. This is the first study to our knowledge to demonstrate how a single gene can act differently in two cell types to induce the same form of cancer. Using IKK beta knock-out mice, Dr. Karin's team determined that IKK-beta assists tumor growth via different mechanisms in different types of cells - through subversion of the programmed cell death that would otherwise prevent tumor formation in epithelial cells and promotion of tumor development through inflammation in myeloid cells. Karin states that "We've shown how tumors arise from chronic infection and inflammation that act together with chemical carcinogens." For More Information Contact: Michael KarinDepartment of Pharmacology Leichtag Biomedical Research Building, Room 214 La Jolla, CA 92093-0723 Tel: 858-534-1361 Email: To learn more about this research, please refer to the following sources:
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118(3):285-296. 
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