Center Overview
Overall Aim: The Seattle TREC Center will elucidate the pathways linking components of energy balance to the cancer process using several different study designs, with the transdisciplinary contributions of scientists from medicine, cell biology, animal models, epidemiology, nutrition, gastroenterology, molecular biology, obesity, endocrinology, obesity, cardiology, immunology, biostatistics, mathematics, exercise physiology, and behavioral science. The overarching theme of the Seattle TREC Center is to determine the mechanisms by which energy balance modifies and influences the process of carcinogenesis across the lifespan in a broad range of settings including cell culture, animal models, small-scale human experimental studies, and population-level experimental work.
Projects: In Project 1we will bring together basic research efforts under way in our laboratories in an innovative approach to analyzing the cellular effects of hyperglycemla, hyperinsulinemia, and inflammation on growth, proliferation, and survival pathways relevant to oncogenesis. In Project 2 we will determine, in an animal model, the effects of caloric restriction and exercise, alone and in combination on the carcinogenic response in the mammary gland and on the mechanisms by which changes in energy balance modulate the development of cancer. In Project 3 we will investigate the metabolic and cancer biomarker response to experimental high and low glycemic load diets in lean and obese teenagers and young adults in a crossover clinical trial design. In Project 4, within a randomized controlled trial, we will investigate the effects of dietary weight loss and exercise, alone and together, on biomarkers of inflammation and DNA damage and repair, and the influences of genetic polymorphisms on these associations. In Project 5 we will test a worksite obesity prevention intervention in a geographic area with a large representation of low income and minority individuals, to determine whether the intervention has any impact on body mass index and markers of insulin resistance and inflammation. Our novel laboratory work will include testing intervention effects on serum proteomics and, in a developmental project, on metabolomics, in order to identify biological signals of dietary, exercise, and adiposity.
Significance: Our investigators have a wealth of expertise in the components of the energy balance and cancer equation, and will provide important scientific leadership, training, and contributions to the overall TREC program.
Project 1: Mechanisms Linking Nutrient Supply & Cell Cycle Survival
Project Leader: David Hockenbery, MD
Overall Goal: Nutrient availability affects cell growth, proliferation, and survival. Apart from the knowledge of pancreatic beta cells, skeletal myocytes, adipocytes and hepatocytes, there is a dearth of information about how cells respond to positive energy balance in the whole animal. Using endothelial cells as a prototypic cell lineage that is resistant to transformation, we will characterize cellular responses to the availability of a nutrient source, glucose, in excess of metabolic requirements (relevant to Projects 2, 3). High concentrations of external glucose trigger an autoregulatory mechanism to limit both glucose uptake and growth factor signaling, while stimulating intracellular pathways that regulate cell proliferation and apoptosis (examined in Project 2). Specifically, we have found that incubation of primary endothelial cells in 25 mM glucose induces c-myc transcription, activation of NF-kB pro-inflammatory pathways and down regulation of PI3-K/Akt signaling (relevant to Projects 2, 3, 4) in this cell type.
Specific Aim: These findings extend a growing appreciation that oncogenes, tumor suppressor genes, and signal transduction pathways are tightly coupled to changes in nutrient availability and energy metabolism. Having established how proliferative responses are coupled to nutrient excess in cells that resist transformation, we will investigate how primary mammary epithelial cells respond to excess glucose availability. We hypothesize that cells that are susceptible to neoplastic transformation will exhibit distinct identifiable responses to nutrient excess that favor cell proliferation. Finally, we will determine whether immortalized, initiated mammary epithelial cells exhibit heightened sensitivity to the effects of glucose excess, providing an epigenetic mechanism for tumor promotion.
Significance: This project addresses key questions for obesity and cancer risk: how nutrient excess is coupled to changes in cell proliferation and survival, and at which point in carcinogenic progression energy balance becomes critical. Insights gained from these investigations will provide novel frameworks for analyzing the effects of obesity on site-specific cancers in animal models and human populations (relevant to Projects 2, 3, 4, 5).
Project 2: Energy Balance and Cancer: Markers and Mechanisms in Rats
Project Leader: Henry Thompson, PhD
Overall Goal: The goal of this project is to determine the effects of controlling weight gain by energy restriction, physical activity, or their combination on the carcinogenic process in an experimental model for breast cancer, and to assess how dietary carbohydrate availability modulates responses as outlined in the followings aims.
Specific Aims:
- Aim 1. Determine the effects of energy restriction or physical activity alone or in combination on the carcinogenic response in the mammary gland and on candidate markers for cancer risk. This model is built on the human model in Project 4 but extends observation to related pathways/processes in the target tissue. This work will be conducted using a well-characterized rodent model for breast cancer and a rodent exercise device newly developed by our laboratory in which a variable-speed, motorized activity wheel is linked, under computer control, to a food pellet dispenser so that physical activity behavior is maintained by positive food reward. Effects of these interventions on the carcinogenic process, on factors involved in glucose homeostasis, and on indicators of inflammation and oxidative damage will be measured. As in Project 1, we will seek to determine how cell proliferation, apoptosis, and angiogenesis are modulated.
- Aim 2. Assess the effect of carbohydrate availability on the carcinogenic response and systemic biomarkers when weight control is mediated by energy restriction and observe pathways and processes in the target tissue. There is considerable speculation but few experimental data to inform the debate about the consequences on disease risk of popular weight loss/maintenance diets that differ in carbohydrate availability. Preliminary studies have established the feasibility of feeding the same diets used in the human feeding study proposed in Project 3 in our pre-clinical animal model.
- Aim 3. Investigate candidate mechanisms and markers using genomic and proteomic technologies in order to elucidate target pathways for prevention. Human beings vary in the amount (dose) of energy restriction or physical activity in which they engage to control weight. Available pre-clinical data indicate that different mechanisms may underlie the prevention of cancer by these interventions depending on intervention dose. cDNA microarray analyses will be used to detect differences in the pathways induced in response to energy restriction or physical activity dose, and proteomic technologies performed in Core C will be employed to discover serum biomarker profiles that reflect the modulation of the carcinogenic response by these interventions.
Project 3: Glycemic Load & Obesity Effects on Cancer Biomarkers
Project Co-Leaders: Marian Neuhouser, PhD and Johanna Lampe, PhD
Background/Overall Goal: Nearly two-thirds of the adult population of the United States is overweight or obese. A growing body of evidence suggests that obesity increases risk for several common cancers. Hyperinsulinemia and altered levels of adipocyte hormones, insulin-like growth factors, and markers of inflammation often accompany obesity and may provide the mechanistic explanation for these observed associations of obesity with cancer. IGF-1 inhibits apoptosis and stimulates proliferation and both insulin leptin are mitogenic. On the other hand, obesity inhibits adiponectin, which has been associated with both the inflammatory response and carcinogenesis. Dietary patterns are related to the synthesis, metabolism, and distribution of these biomarkers. For example, diets can be characterized relative to their influence on the postprandial glucose response. Diets rich in simple sugars and refined carbohydrates have a high glycemic index because they produce a rapid rise in blood glucose. Foods such as meats, legumes, and high-fiber fruits and vegetables produce a low rise in blood glucose and have a low glycemic index. Despite the plethora of scientific papers suggesting that high-glycemic-index foods increase cancer risk, very few intervention studies in humans have evaluated the action of low and high glycemic foods on biomarkers of cancer risk.
Specific Aim: We propose a randomized, controlled crossover feeding trial in 88 lean (BMI<25) and obese (BMI>30) men and women. Participants will be randomized to consume either a low- or high-glycemic-load diet for 4 weeks, followed by a 4-week washout period, after which they will cross over to the other arm. Blood samples will be collected at the beginning and end of each diet period and assayed for insulin, glucose, IGF-1, 1GFBP3, leptin, adiponectin, C-reactive protein, serum amyloid A, and interleukin-6.
Significance: This study will provide a rigorous test of common dietary patterns in humans that will allow us to directly examine diet-related mechanisms of obesity and biomarkers of carcinogenesis. Importantly, by recruiting both lean and obese persons, we will be able to examine whether there is a differential response to the high- and low- glycemic load diets for lean versus obese individuals. This study will provide data of immediate clinical and public health benefit.
Project 4: Exercise and Diet: Biomarkers and Mechanisms in Humans
Project Co-Leaders: Cornelia Ulrich, PhD and Anne McTiernan, MD, PhD
Background/Overall Goal: Physical activity and nutrition alter cancer risk, with possible mechanisms including effects on inflammation, insulin-like growth factors, insulin resistance, steroid hormones, and lipid metabolism. An unexplored possible mechanism linking energy balance to cancer risk includes effects on DNA repair capacity. Defects in DNA repair function are clearly carcinogenic, and intriguing preliminary evidence suggests that regular exercise results in an adaptive response of enhanced antioxidant defenses and DNA repair. DNA repair capacity also plays a central role in that the inflammatory process can increase oxidative DNA damage.
Specific Aim: This research will address the intersection of diet, physical activity, weight, and body composition on biomarkers of cancer risk. The research will be ancillary to a funded human clinical trial of exercise and caloric restriction. Primary specific aims are to investigate the separate and combined effects of 1 year of exercise and/or a reduced-calorie diet among 503 postmenopausal women on
- Biomarkers of inflammation (C-reactive protein, serum amyloid A, interleukin-6);
- DNA damage sensitivity and DNA repair capacity; and
- Plasma protein patterns (proteomics).
Investigations of intervention effects on plasma protein patterns will enable us to identify possible new mechanisms linking exercise or a reduced-calorie diet to carcinogenesis. As secondary outcomes, we will evaluate intervention effects on gene expression of DNA repair genes and on biomarkers of obesity. Further, we will investigate whether intervention effects differ by body mass index or body composition prior to the intervention or are dependent on changes in body composition during the course of interventions. Finally, we will explore whether genetic characteristics modify the intervention effect. The proposed measurements will be complemented by biomarkers already planned within the funded parent grant (insulin, IGFI , IGFBP3, steroid hormones) and allow for investigations of interactions with the newly investigated pathways. Thus, Project 4 provides a comprehensive and cost-effective approach for investigating the independent and combined effects of exercise and caloric restriction on biomarkers of cancer risk among humans. Close collaborations with Projects 2, 3, and 5 will enhance our understanding of the mechanistic effects linking exercise and energy balance to cancer risk.
Project 5: Preventing Obesity in Low Income Working Adults
Project Leader: Shirley Beresford, PhD
Background/Overall Goal: Reducing the prevalence of obesity in the population is one of the Healthy People 2010 goals, and active vigilance is required in all age groups in preventing and reversing overweight and obesity. On a population basis, the prevalence of overweight is associated with a myriad of influences, including social, behavioral, cultural, and environmental factors, as well as genetic and physiological factors. For a majority of overweight individuals, restoring a balance between energy intake and expenditure is difficult, and therefore there is an increasing emphasis on preventing obesity on a population level. The longer-term goal of this research is to prevent further increase in rates of obesity in the population. This project has the potential to influence the worksite environment in ways informed by this Center's other projects. In the adult population of working age, a majority of the day is spent at the worksite, suggesting that interventions at the worksite level may offer the opportunity for success in this age group.
Design: We will develop and test a comprehensive intervention with simple messages that will integrate changes in dietary intake with changes in energy expenditure, while simultaneously modifying structural and environmental factors to promote social support and opportunities for behavioral change. We will recruit and randomize 28 worksites, from the 98144 zip code area, to a 2-year intervention in which we will build a physical activity intervention combining increased daily physical activity and regular, structured exercise; build a dietary intervention that will promote lower calorie intake; and increase worksite access to both healthy foods and physical activity.
Specific Aims: Our primary aim is to evaluate the effectiveness of the intervention in reducing or maintaining body mass index in a randomized controlled trial of worksites. We will compare changes in body mass index in intervention versus control worksites using two cross-sectional surveys at baseline and follow-up.
Significance: The impact of the intervention on biomarkers related to nutritional intake, obesity, inflammation, insulin resistance, and adipokines will be estimated in a subset of employees. Our team has considerable experience with interventions at the worksite level and substantial expertise in obesity prevention. We anticipate that this project will yield important contributions to the implementation of obesity prevention and will be informed by study results obtained in Projects 1, 2, 3, 4.
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