Obesity and Cancer Mechanisms: Cancer Metabolism

Abstract

Obesity is a risk factor for cancer development and is associated with poor prognosis in multiple tumor types. The positive energy balance linked with obesity induces a variety of systemic changes including altered levels of insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, and cytokines. Each of these factors alters the nutritional milieu and has the potential to create an environment that favors tumor initiation and progression. Although the complete ramifications of obesity as it relates to cancer are still unclear, there is convincing evidence that reducing the magnitude of the systemic hormonal and inflammatory changes has significant clinical benefits. This review will examine the changes that occur in the obese state and review the biologic mechanisms that connect these changes to increased cancer risk. Understanding the metabolic changes that occur in obese individuals may also help to elucidate more effective treatment options for these patients when they develop cancer. Moving forward, targeted clinical trials examining the effects of behavioral modifications such as reduced carbohydrate intake, caloric restriction, structured exercise, and/or pharmacologic interventions such as the use of metformin, in obese populations may help to reduce their cancer risk.

Fig 1.

The signaling of obesity. (A) Changes in the size of adipose depots affect systemic homeostasis and lead to increases in insulin (INS), insulin-like growth factor (IGF), leptin, inflammatory cytokines, and result in decreased levels of adiponectin. IL-6, interleukin 6. (B) These signaling molecules activate cell surface receptors and drive signaling through the Janus kinase (JAK)/signal transducers and activators of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) signaling pathways, all of which are frequently altered in cancer. By chronically activating metabolic signaling cascades, the obese state lowers the barrier for oncogenic transformation by driving cell growth and proliferation, and resisting apoptosis. It is these functions that make components of these signaling pathways some of the most frequently altered in human cancers. Glut4, glucose transporter type 4; GP130, glycoprotein 130; IGFR, insulin-like growth factor receptor; IL6R, interleukin 6 receptor; INSR, insulin receptor; ObR, leptin receptor.