The most important questions in cancer research and clinical oncology—Question 2–5. Obesity-related cancers: more questions than answers

Obesity is recognized as the second highest risk factor for cancer. The pathogenic mechanisms underlying tobacco-related cancers are well characterized and effective programs have led to a decline in smoking and related cancers, but there is a global epidemic of obesity without a clear understanding of how obesity causes cancer. Obesity is heterogeneous, and approximately 25% of obese individuals remain healthy (metabolically healthy obese, MHO), so which fat deposition (subcutaneous versus visceral, adipose versus ectopic) is “malignant”? What is the mechanism of carcinogenesis? Is it by metabolic dysregulation or chronic inflammation? Through which chemokines/genes/signaling pathways does adipose tissue influence carcinogenesis? Can selective inhibition of these pathways uncouple obesity from cancers? Do all obesity related cancers (ORCs) share a molecular signature? Are there common (over-lapping) genetic loci that make individuals susceptible to obesity, metabolic syndrome, and cancers? Can we identify precursor lesions of ORCs and will early intervention of high risk individuals alter the natural history? It appears unlikely that the obesity epidemic will be controlled anytime soon; answers to these questions will help to reduce the adverse effect of obesity on human condition.