Obesity and cancer: new evidence continuous update project

Obesity and cancer: associations and underlying mechanisms

Stephen Hursting

University of North Carolina, Chapel Hill, Estados Unidos de América

Introduction: The prevalence of obesity, an established risk and progression factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Globally, meta-analyses and systematic reviews conducted by the World Cancer Research Fund and American Institute for Cancer Research indicate obesity is strongly linked with cancers of the breast (in postmenopausal women), colon, pancreas, endometrium, ovaries, stomach, esophagus, kidney, prostate (advanced) and liver. Obese cancer patients also often have poorer prognoses, reduced response to standard treatments and are more likely to develop metastatic disease than normoweight individuals. Unfortunately, the mechanisms underlying the obesity and cancer connection are poorly understood, and new targets and strategies for reducing the impact of obesity on the cancer burden are urgently needed given the World Health Organization estimates there are currently 1.9 billion overweight or obese adults worldwide. Development: Several energy balance– related host factors are known to influence tumor development, progression and/or treatment responsiveness, and these have been implicated as key contributors to the complex effects of obesity on cancer. These host factors include leptin, adiponectin, steroid hormones, cytokines associated with inflammation, and metabolic hormones such as insulin and insulin-like growth factor–1. Each of these host factors will be considered in the context of obesity and cancer, and future mechanism-based research directions in this field will be discussed. We will also discuss lessons learned from our recent integration of preclinical studies with clinical trials and epidemiologic studies to accelerate the translation of research on preventing obesity-related cancers. In particular, our recent work suggests that moderate weight loss may be insufficient to reverse the cancer-associated metabolic and inflammatory perturbations that occur with chronic obesity. We have found in genetically-engineered mouse models and human studies that chronic obesity results in epigenetic reprogramming, including global changes in DNA and histone methylation and microRNA biogenesis, and have established that normalization of weight is insufficient to reverse the obesity-induced epigenetic and metabolic changes and normalize cancer susceptibility. Our transdisciplinary studies suggest that combining weight loss regimens with interventions that target the obesity-associated epigenetic, metabolic and/or inflammatory changes may be an effective strategy for breaking the obesity-cancer link. Conclusion: Obesity has emerged as an important risk and progression factor for many cancers, and mechanism-based targets and intervention strategies are urgently needed to reduce the impact of obesity on cancer burden. Several mechanistic targets have recently emerged, including growth factor signaling related to insulin resistance, obesity-associated inflammation, and epigenetic reprogramming. Key words: obesity; cancer; meta-analyses; metabolism; inflammation.