Obesity, defined by body-mass index over 30.0, influences more than 30% of American adults and is associated with increased incidence and/or bad prognosis of various cancers including esophagus, pancreas, colon and rectum, breast, and endometrium etc. Obesity contributes directly to the 34,000 new cancer cases in men (4% of all cancer) and 50,500 in women (7% of all cancer) in 2007, based on the NCI Surveillance, Epidemiology, and End Results (SEER) data. In addition, obesity increases the risk for many different types of cancer including breast cancer and decreases patient survival and is associated with bad outcome. Obesity always correlates with increased basal level inflammation. It is unknown, however, if obesity-associated inflammation promotes cancer progression and what is the molecular sensor for obese tumor microenvironment. Here we found that sterile inflammation–a type of inflammation without clear infections and activated by danger signals released by tissue damage–in the obese tumor microenvironment, led to Nlrc4-inflammasome activation. We found that interleukin-1beta is the major downstream mediator for Nlrc4-inflammasome activation that provides a pro-inflammatory signal to be required for tumor growth in obese mice, but not in normal-weight ones, by promoting angiogenesis in obese tumors. Our goals are to understand how obesity contributes to cancer progression, and to develop treatments to obese cancer patients.
The proposed study has ground-breaking impacts on basic cancer biology and cancer therapy to obese cancer patients. For cancer biology, we identified the molecular sensor in obese tumor microenvironment and aim to detect ‘danger signal’ from obese tumors, which, in turn, promotes cancer progression via activation of interleukin-1beta. For cancer therapy, given that ~30% Americans are obese and many cancer types are influenced by obesity, our study will have big impact on cancer patients. Anakinra is a known decoy receptor to inhibit interleukin-1 receptor-mediated signaling and has been improved drug to treat rheumatic arthritis. Caspase-1 (the major enzyme for inflammasome-mediated interleukin-1beta activation) inhibitors have been in several clinical trials. In addition, we found that metformin reduces obesity-associated tumor growth. These drugs can be easily and quickly adapted for treating obese cancer patients, together with current standard care for cancer patients.