Case Western Reserve University
Principal Investigator Dr. Nathan Berger
Overal Aim: The overall goals of the Case Center for Transdisciplinary Research on Energetics and Cancer are defined organizationally and scientifically. Organizationally, we seek: 1) to establish a productive, durable program for transdisciplinary research on energetics and cancer at Case Comprehensive Cancer University; 2) to provide pilot project support and training opportunities for new and established scientists who can conduct integrative research on energetics, energy balance, and their consequences relative to cancer across the continuum from cancer causation and prevention through survival; and 3) to establish collaborative relations with investigators throughout our university and at other TREC Centers and universities to maximally and synergistically utilize resources to significantly impact problems associated with obesity and cancer. Scientifically, we will conduct a spectrum of mechanism-based laboratory, clinical, and population-based studies to identify targets for prevention and control of obesity and interruption of the linkage between obesity and cancer. The scientific aims are defined by three programs and two pilot projects that are highly interactive and are supported by three TREC core facilities and by the 17 Comprehensive Cancer Center core facilities.
Project 1 seeks to determine the intestinal tumor-inducing effect and molecular signaling pathways associated with high-fat diet versus obesity in unique strains of mice with chromosomal substitutions rendering them susceptible or resistant to the obesigenic effects of high-fat diets. Project 2 will examine candidate gene variance and haplotype, associated biomarkers, and insulin-resistance syndrome-related serum markers to understand how insulin-resistance syndrome, related genes, and dietary factors work in concert in the etiology of human colon neoplasia. Project 3 will investigate determinants of obesity and metabolic dysfunction during the critical life-transition period of adolescence. This study will capitalize on a unique population cohort followed as part of the Cleveland Children's Sleep and Health Study and will investigate sleep phenotype and sleep disturbances as novel and important determinants of obesity and its relation to metabolic dysfunction.
Summary/Significance: Pilot Project 1 will investigate the role of ER stress pathways linking the metabolic stress of obesity to development of insulin resistance, its consequences, and the identification of molecular targets for interrupting these pathways to prevent health consequences of obesity. Pilot Project 2 will take advantage of a unique new metabolomic facility at Case to determine whether a metabolic signature can be identified, first in mice and then in humans, linking obesity to cancer susceptibility.
Project Leader: Sanford Markowitz, MD, Ph.D.
Overall Goal: Colon cancer is the second leading cause of cancer death in the U.S., and in the obese population the risk of developing colon cancer is elevated twofold, which is among the largest increases in risk seen for any obesity-associated cancer. The goals of this project are to demonstrate that increased colon cancer risk is associated with obesity per se, and not with increased dietary fat intake; to elucidate the role of increased IGF1 signaling as a mediator of the obesity-associated increased colon cancer risk; and to further identify key genes whose expression within the human colon is altered by obesity and by altered IGF1 signaling. This project is based on the unique development by our group of C57b1/6-derived chromosome-substituted mouse strains that are either obesity- sensitive or obesity-resistant when placed on a high fat diet, and also on the unique finding by our group of mutational activation of IGF1 signaling in frank colon cancers due to mutational activation of PIK3CA, an early transducer of IGF1 signaling.
Specific Aims: Our aims will be:
- To compare the intestinal tumor-promoting effects of a high-fat diet in mice that become obese on this diet (obesity-sensitive) versus mice that do not develop obesity (obesity-resistant), when these mice are engineered to carry the intestinal tumor-inducing APC mutant Min allele.
- To employ expression microarrays to identify those mouse genes whose expression in the intestine is regulated by obesity—that is, genes whose expression is modulated by a high-fat diet only in obesity-sensitive but not in obesity-resistant mice. To further identify which of these obesity-regulated genes demonstrates altered expression in a microarray comparison of colonic epithelium from obese versus non-obese humans.
- To construct transgenic mice in which an activated mutant PIK3CA gene is specifically targeted for expression in the intestine. Further, by comparing tumor development in obese versus non-obese mice carrying this transgene, to determine whether the tumor promoting effect of activated IGF1/PIK3CA pathway signaling is epistatic with (in the same pathway with) or is independent of the tumor-promoting effects of obesity.
- To compare the activation of IGF1 signaling in normal human colon mucosa from obese versus non-obese individuals by using quantitative immunohistochemistry to compare in these tissues the levels of phosphorylation of key IGF1-activated signaling molecules: IGF1R, AKT and mTOR. Moreover, to identify those genes whose expression in the mouse intestine is altered by increased IGF1/PI3KCA signaling, and to further identify if this "IGF1 signaling signature" of altered gene expression is evidenced on microarray comparison of gene expression in the colons of obese versus non-obese humans.
Project Leader: Li Li, MD, Ph.D.
Overall Goal: Increasing evidence from both model systems and epidemiologic studies support that insulin resistance resulting from long-term energy imbalance plays an important role in colon carcinogenesis. The fact that the incidences of obesity, insulin resistance syndrome, and type 2 diabetes are escalating at epidemic pace worldwide makes the exploration of the insulin resistance-colon neoplasia hypothesis a subject of pressing priority. We hypothesize that candidate genes and associated biomarkers in the insulin-growth hormone-insulin-like growth factor (IGF)-insulin receptor substrate 1 (IRS-1) axis, adipogenesis pathway (adiponectin, and peroxisome proliferator-activated receptor-?), and dietary factors may work jointly to drive the development of insulin resistance syndrome, and subsequently, the development of colon adenomatous polyps, established precursors of colon cancer.
Design: We will conduct a screening coIonoscopy-based incident case-control study to address the insulin resistance syndrome-colon polyp hypothesis by prospectively recruiting 750 incident colon polyp cases and 750 frequency-matched controls. We will determine the candidate gene variants and haplotypes, associated biomarkers, and insulin resistance syndrome-related serum markers using blood samples, and collect dietary and lifestyle risk factor information using questionnaires. We will analyze the resulting information using novel statistical models to gain comprehensive understanding of the link between insulin resistance syndrome and colon polyps.
Specific Aims: Specifically, we will:
- Investigate the impact of insulin resistance syndrome as an internal entity on colon polyps;
- Examine the impact of candidate genes and associated biomarkers in the insulin-GH-IGF-IRS axis and adipogenesis pathway on colon polyps;
- Evaluate the association of dietary patterns, glycemic index and glycemic load with colon polyps;
- Synthesize the information on candidate genes, biomarkers, and diet by looking at their joint effects on colon polyps; and
- Comprehensively evaluate these factors' potential direct as well as indirect (mediated by insulin resistance syndrome) impact on colon polyps.
Significance: Our study will contribute to our understanding of how insulin resistance syndrome pathway-related candidate genes and dietary factors might work in concert in the etiology of colon adenomatous polyps. Our study may have profound implication for public health prevention/intervention strategies targeted at the early stages of the colon adenoma-cancer continuum.
Project Leader: Susan Redline, MD, M.P.H.
Overall Goal: Obesity and metabolic dysfunction increase the risk of cancer incidence and mortality. Increases in obesity and associated metabolic dysfunction are likely partly attributable to modem lifestyles characterized by high-fat food intake and reduced physical activity, and such behaviors may begin in childhood. Insufficient sleep, increasingly common in adolescents, has been implicated as a risk factor for both obesity and metabolic dysfunction. In this project, we will define the relationship between a number of host risk factors operating during childhood and adolescence, including insufficient sleep and sleep apnea, to longitudinally measured changes in both weight and biochemical indices of metabolic pathways implicated in cancer. We will capitalize on access to a large population-based pediatric cohort, the Cleveland Children's Sleep and Health Study, in which multiple measures of behavioral, sleep, and biochemical risk factors for obesity have been measured longitudinally.
Design: The sample includes 50 percent former preterm children and 41 percent ethnic minorities, providing opportunities to quantify and identify specific mediators of excess risk of obesity and metabolic dysfunction in vulnerable subgroups. We will study 600 cohort members at ages 16 to 19 years, obtaining current measures of metabolic function that have been implicated in cancer (i.e., sex hormone levels, insulin resistance, adipokines, growth factors). Anthropometric measurements will quantify body weight, stature, and body fat distribution. Risk factor data include standardized assessments of nutritional intake and behavioral risk factors. Subjects also will undergo 5-7 day monitoring of physical activity level and sleep/wake behavior with actigraphy and an overnight sleep study.
Specific Aims: Combining these data with birth data and data collected at a previous 8- to 11-year-old exam will allow us to address the hypothesis that weight gain is largest in adolescents with insufficient sleep, and such effects are independent of other behavioral risk factors; and that metabolic dysfunction is most marked in adolescents with sleep apnea and in those with rapid weight gain. Identification of risk factors for obesity and metabolic dysfunction, and their variation with demography and common behavioral factors, including the novel consideration of sleep behaviors, may help develop targeted interventions for high-risk children and elucidate important pathophysiological pathways that increase risk of several chronic health conditions, including cancer and diabetes.