Biomarkers of obesity inflammation and colon cancer risk

Michigan State University, East Lansing MI

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Abstract

DESCRIPTION (provided by applicant): During the past 20 years, obesity has risen at an epidemic rate in the United States. It is anticipated that with increased obesity colon cancer cases will increase;therefore, research regarding how obesity increases the risk of colon cancer is extremely timely, important and will affect upcoming generations. Adipose tissue secretes hormones and cytokines (adipokines) that may play a role in the development of the systemic inflammatory state associated with obesity and subsequent colon cancer risk. While these hormones/cytokines are critical to normal cellular functioning at homeostatic concentrations, when levels are altered from normal (as in obesity) they may be pathologic. There is increasing interest in utilizing serum analysis of proteins to identify biochemical indicators of a physiological or disease process with clinical utility (i.e., biomarkers) for assessing obesity-associated colon cancer risk. The characterization of a serum biomarker profile represents an important step in the process to describe changes in key mediators that vary with adiposity and may influence colon cancer carcinogenesis. Our laboratory has demonstrated that some serum-derived biomarkers changing with adiposity, including leptin, IL-6, and adiponectin have profound effects on colon epithelial cells. These biomarkers were shown in vitro to induce several phenotypes consistent with colon cancer that translate into promotional signals for colon cancer progression. However, a critical gap exists in our understanding of the overall pattern of changes in the biomarker profile in serum of individuals based on adiposity and how that may translate to obesity associated colon cancer risk. The long-term goal of this research is to understand the pathophysiologic consequences of exposure of the colon to altered concentrations of adipose-derived hormones, growth factors, and cytokines as observed in the obese state. The short-term goal of this work is characterize the serum biomarker profile of either normal or colon cancer patients at various levels of adiposity. The central hypothesis of this proposal is that patterns of proinflammatory proteins in serum will differ among lean (BMI=21), normal (BMI 24-25), and obese (BMI=30) individuals and influence colon cancer carcinogenesis. It is anticipated that upon identification of a pattern, it may become possible to predict individuals with obesity and inflammation-associated risk for colon cancer and target these protein changes in novel therapies for obesity-related colon cancer prevention and progression. We plan to address the central hypothesis of this proposal in two specific aims: 1) establish the differences in serum patterns of proinflammatory markers associated with differences in adiposity (or energy balance) in humans, and 2) identify changes in patterns of proinflammatory markers in serum associated with differences in adiposity (or energy balance) in newly diagnosed early-stage colon cancer patients compared to controls. The research in this application is relevant to public health because it is critical to colon cancer prevention targets to identify and characterize the changes in blood levels of obesity-associated inflammatory mediators that may lead to increased development of cancer. Understanding the changes in biomarkers individuals who are at a lower risk for colon cancer may also lead to risk profiling, specific target identification and prevention strategies.