Inflammation and Cancer: Two Pieces of the Same Puzzle?
During chronic inflammation-induced tumor promotion, an accumulation of inflammatory cells (blue) is detected in the colon. The presence of STAT2 activates the secretion of a number of inflammatory genes, most prominently IL-6. Enhanced IL-6 secretion in turn causes the activation of the STAT3 oncogenic pathway leading to proliferation of pre-malignant cells and, ultimately tumor development.
Chronic inflammation, in Crohn’s disease for example, is a known risk factor for malignant transformation, however the role inflammation plays in cancer initiation is poorly understood. STAT2, an important protein that regulates gene activation, is known to be stimulated by immune factors that inhibit cell growth. STAT2 also has reduced expression in the immune cells of patients with Crohn’s disease, which suggested to Ana Gamero, Ph.D., a former NCI Scholar of the Laboratory of Experimental Immunology, CCR, and now Assistant Professor at Temple University in collaboration with Nancy Colburn, Ph.D. of the Laboratory of Cancer Prevention and her colleagues, that STAT2 may be a key protein in regulating inflammation-induced cancer progression. The results of their studies were recently published in a Cancer Prevention Research article.
To investigate STAT2’s function in inflammation and cancer development, mice lacking STAT2 expression (STAT2 KO) or wild type mice, which express normal levels of STAT2, were exposed to a chemical carcinogenesis regimen to stimulate cancer development. Contrary to their initial hypothesis, the researchers observed that loss of STAT2 actually reduced the levels of inflammation, and thus tumors, in target tissues.
Following drug treatment in the colon, STAT2 KO mice lost less weight than their wild type counterparts, and their tissue samples showed that fewer inflammatory cells had invaded into the colon. Likewise, wild type animals had more, larger tumors and more destruction of the normal colon architecture. By the end of the 16-week study, 60 percent of the wild type animals had succumbed to cancer while all the STAT2 KO mice survived. These data indicate that STAT2 promotes inflammation and tumor progression in the colon.
The researchers wanted to determine how STAT2 controls inflammation. Since STAT2 regulates gene transcription, the gene expression profiles in colon tissue of treated wild type and KO animals were compared. Loss of STAT2 resulted in a decrease in inflammatory factor genes, including IL-6, and in known cancer promoting genes such as STAT3. Reduced secretion of IL-6 and decreased staining for active STAT3 were observed in STAT2 KO colon tissue verifying the importance of these changes in gene expression.
Similar to the colon cancer model, STAT2 KO mice treated with a skin carcinogenesis protocol had a delayed onset of tumor formation and fewer tumors than wild type animals. Studies in skin cancer cell lines isolated from wild type and STAT2 KO mice further demonstrated that secreted IL-6 and active STAT3 were more abundant in cells expressing STAT2. In fact, exposing STAT2 KO cells to additional IL-6 caused STAT3 activation, indicating that the release of this pro-inflammatory signaling protein, which is under the control of STAT2, is necessary for STAT3 activation and tumor progression.
The work by Colburn and colleagues reveals that STAT2 is a critical component in the process of inflammation-stimulated cancer formation. Surprisingly, STAT2 works as a promoter of tumorigenesis and not as an inhibitor. By increasing the production and release of inflammatory factors such as IL-6, STAT2 creates an environment that permits the activation of pro-cancer proteins including STAT3. Thus early targeting and inactivation of STAT2 may delay or prevent tumor development.Summary Posted: 12/2010
Cancer Prev. Res. 2010 3(4):495-504 PubMed Link