Professor Stephen D. Hursting
Department of Nutritional Sciences, The University of Texas at Austin and Department of Molecular Carcinogenesis, the University of Texas MD Anderson Cancer Center, USA
Stephen D. Hursting is Professor and Chair of the Department of Nutritional Sciences at the University of Texas at Austin. He is also the McKean-Love Chair of Nutrition, Molecular and Cellular Sciences at the University of Texas and is Professor of Molecular Carcinogenesis at the UT-MD Anderson Cancer Center. Dr Hursting earned his PhD in nutritional biochemistry and MPH in nutritional epidemiology from the University of North Carolina, and he completed postdoctoral training in molecular carcinogenesis and cancer prevention at the NCI. Prior to joining the University of Texas in 2005, Dr Hursting was Deputy Director of the NCI’s Office of Preventive Oncology and Chief of the NCI’s Nutrition and Molecular Carcinogenesis Laboratory Section. His research, which has resulted in over 150 publications, centers on diet-gene interactions relevant to cancer prevention, particularly the molecular, metabolic and inflammatory mechanisms underlying obesity-cancer associations.
Obesity, energy balance and cancer prevention: Mechanistic insights from transdisciplinary studies
The prevalence of obesity, an established risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Unfortunately, the mechanisms underlying the obesity and cancer connection are not well understood, and new targets and strategies for offsetting the impact of obesity on cancer risk and/or progression are urgently needed. We have established that calorie restriction (CR), the most commonly recommended dietary strategy for preventing or reversing obesity, inhibits tumor development and progression in a variety of animal models. In contrast, diet-induced obesity enhances tumorigenesis in many of these same models. We have shown in a series of transgenic model systems and microarray studies that the insulin/insulin-like growth factor (IGF)-1 pathway appears central to many of the anti-cancer effects of CR and pro-cancer effects of obesity. Using AZIP/F1 transgenic mice (which lack white adipose tissue but have high levels of insulin and IGF-1), and liver-specific IGF-1-deficient mice, we have reported that elevated IGF-1/insulin resistance/inflammation (which typically accompany obesity), independent of the adipose tissue per se, appear to be the important targets for disrupting the obesity-cancer link. Also, genetic and pharmacologic approaches suggest the Akt/mammalian target of rapamycin (mTOR) pathway (downstream of insulin and IGF-1 receptors) provides an important target for disrupting the obesity-cancer link. A better understanding of the mechanisms underlying the energy balance-cancer link will facilitate the development of novel prevention and treatment strategies for offsetting the effects of obesity on cancer.
Dietary energy balance modulation of murine pancreatic cancer: The role of insulin-like growth factor-1
New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant murine spontaneous and orthotopically transplanted models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF) 1−dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+mice and K5- cyclooxygenase (COX)-2 transgenic mice, calorie restriction, relative to overweight- or obesity-inducing diet regimens, decreased serum IGF-1, tumoral Akt/mammalian target of rapamycin (mTOR) signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC); and increased pancreatic tumor-free survival. Serum IGF-1, Akt/ mTOR signaling, and orthotopically transplanted PDAC growth (multiple models) were decreased in liver-specific IGF-1− deficient mice (versus wild-type mice), and rescued with IGF-1 infusion. In addition, rapamycin and metformin inhibited mTOR and mimicked many of the anticancer effects of calorie restriction. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced either by mutant Kras and Ink4a deficiency (the most common genetic alterations in human pancreatic cancer) or overexpression of COX-2 (associated with human pancreatitis, which increases PDAC risk by up to 55-fold). Furthermore, IGF 1 and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.