Inflammation: Linking Obesity with Cancer Risk

There is a plethora of scientific data associating obesity to cancer risk in the United States (1). This represents a major problem in this country, as an estimated 34% of Americans over the age of 20 are considered obese. This is according to results from the 2005-2006 National Health and Nutrition Examination Survey (2). Data from the survey also suggested that obesity prevalence is on the rise in comparison to previous decades. Sedentary lifestyle, poor diet, genetics, and combinations thereof, are associated with obesity. However, what links obesity and cancer risk has been unclear. A new study published in the journal Cell used a liver cancer mouse model to study what may associate the two (3).

The author's rationale for using a liver cancer model was due to a study demonstrating that a BMI of 35-40 increases the relative risk of liver cancer 4.52 fold (4). Mice were treated with a chemical, diethylnitrosamine (DEN), which sensitizes them to hepatocarcinogenesis, or liver cancer. The authors then placed the treated mice on a low or high fat diet and monitored their livers for the development of tumors. Mice genetically predisposed to obesity by a lack of the gene leptin were used in the study as well, such that that both dietary and genetically induced obesity could be addressed.

Interestingly, the numbers of tumors per liver, tumor size, and the incidence of tumor formation, were increased in the high fat diet group compared to mice on the normal diet. Mice with genetically induced obesity also had a significantly higher number of liver tumors compared to wild type mice after DEN treatment. This suggests that no matter the route to obesity, genetic or diet, cancer risk may be increased.

The authors observed increased levels of the inflammatory cytokine interleukin-6 (IL-6) and an increase in tumor necrosis factor alpha (TNF-a) messenger RNA. Inflammatory signaling has previously been postulated to promote oncogenesis in certain situations (5). To assess the contribution of these inflammatory cytokines to carcinogenesis in the liver cancer model presented, the authors used mice deficient for IL-6 or the TNF-a receptor under the same conditions described above.

Deficiency for IL-6 or TNF-a receptor reduced tumor formation in the high fat diet mice close to that of mice on the normal diet after DEN treatment. This suggests that a high fat diet leading to obesity may increase the risk of cancer through, but not necessarily limited to, the inflammatory cytokines IL-6 and TNF-a. More work will need to be done to verify that this is indeed a physiological mechanism of increased cancer risk in humans. The study does however offer promise for a potential therapeutic strategy intargeting liver cancer related to obesity.

References:

1. Obesity and Cancer: Questions and Answers. http://www.cancer.gov/cancertopics/factsheet/Risk/obesity. Accessed 01/26/2010

2. Prevalence of overweight, obesity and extreme obesity among adults: United States, trends 1976-80 through 2005-2006. http://www.cdc.gov/nchs/data/hestat/overweight/overweight_adult.htm. Accessed 01/26/2010

3. Park, EJ et al. 2010. Cell. 140; 197-208

4. Calle, E.E., Rodriguez, C., Walker-Thurmond, K., and Thun, M.J. N. Engl. J. Med. 348, 1625-1638

5. Schetter, AJ. Carcinogenesis 2010 31(1):37-49