2 immune-system proteins linked to colitis-associated cancer

Karin, Distinguished Professor of Pharmacology and Pathology and member of the Moores UCSD Cancer Center, and his team used genetic tools to demonstrate in mice that a cytokine called Interleukin 6 (IL-6), is an important regulator of tumor production during CAC development, and that its molecular effects are largely mediated by the transcription factor STAT3 in cancer cells.

Their latest study – which is also the first to establish the cancer-promoting function of STAT3 in a validated mouse model of human cancer – will be published in the February 3 on-line edition of the journal Cancer Cell.

Recurrent inflammation and chronic infections contribute to a large number of different cancers including CAC which occurs in people suffering from chronic colitis, a common inflammatory bowel disease, putting them at very high risk for cancer. Cytokines – small proteins released by immune-system cells – have been suggested to drive early tumor growth by stimulating the growth and survival of pre-malignant cells.

In previous work, Karin's team showed that activation of a pro-inflammatory protein called NF-kB stimulates the proliferation of premalignant epithelial cells in CAC, giving rise to malignant growths in the colon. Interestingly, NF-kB in colonic epithelial cells promotes the development of cancer, not through inflammation, but through inhibition of apoptosis or cell death. On the other hand, NF-kB in the immune cells promotes cancer by enhancing inflammation, mostly by controlling the expression of pro-inflammatory cytokine expression. One of these cytokines was thought to be IL-6.

“IL-6 fosters chronic inflammation and malignant cell survival and growth by regulating the survival of T cells, white blood cells that direct the body's immune system,” Karin said.

The proliferative and survival effects of IL-6 are largely mediated by the transcription factor STAT3, first suggested to have a cancer-promoting function by James Darnell at Rockefeller University in New York. The new work, which provides the first genetic evidence for the critical role of STAT3 in cancer using a mouse model of human cancer, also suggests that IL-6 and Stat3 constitute useful targets for the prevention and treatment of CAC, Karin added. The researchers showed that ablation of STAT3 in intestinal epithelial cells effectively inhibited CAC induction and growth in mice.

Colorectal cancer is one of the most common fatal malignancies worldwide, and almost half of all affected individuals die from the disease. Patients with inflammatory bowel disease, such as ulcerative colitis, are at a higher risk of developing colorectal cancer.