Biomarkers of obesity inflammation and colon cancer risk

描述（由申请人提供）： 在过去的20年里，肥胖症在美国以流行病的速度上升。预计随着肥胖的增加，结肠癌病例将增加;因此，关于肥胖如何增加结肠癌风险的研究非常及时，重要，并将影响后代。脂肪组织分泌激素和细胞因子（脂肪因子），可能在与肥胖和随后的结肠癌风险相关的全身炎症状态的发展中发挥作用。虽然这些激素/细胞因子在稳态浓度下对正常细胞功能至关重要，但当水平从正常改变时（如肥胖），它们可能是病理性的。人们越来越关注利用蛋白质的血清分析来鉴定具有临床实用性的生理或疾病过程的生化指标（即，生物标志物）用于评估肥胖相关的结肠癌风险。血清生物标志物谱的表征代表了描述随肥胖而变化并可能影响结肠癌致癌作用的关键介质变化的过程中的重要步骤。我们的实验室已经证明，一些血清来源的生物标志物随着肥胖而变化，包括瘦素，IL-6和脂联素对结肠上皮细胞有深远的影响。这些生物标志物在体外显示出诱导与结肠癌一致的几种表型，其转化为结肠癌进展的促进信号。然而，在我们对基于肥胖的个体血清中生物标志物谱的总体变化模式以及如何转化为肥胖相关的结肠癌风险的理解中存在着一个关键的差距。本研究的长期目标是了解结肠暴露于改变的脂肪源性激素、生长因子和细胞因子浓度的病理生理后果，如在肥胖状态下所观察到的。这项工作的短期目标是表征不同肥胖水平的正常或结肠癌患者的血清生物标志物谱。该建议的中心假设是血清中促炎蛋白的模式在瘦（BMI=21）、正常（BMI 24-25）和肥胖（BMI=30）个体中不同，并影响结肠癌的致癌作用。预计在识别模式后，可以预测具有肥胖和炎症相关结肠癌风险的个体，并在用于肥胖相关结肠癌预防和进展的新疗法中靶向这些蛋白质变化。我们计划在两个具体目标中解决该提议的中心假设：1）建立与人类肥胖（或能量平衡）差异相关的促炎标志物血清模式的差异，以及2）确定与新诊断的早期结肠癌患者与对照组相比的肥胖（或能量平衡）差异相关的血清促炎标志物模式的变化。本申请中的研究与公共卫生相关，因为识别和描述肥胖相关炎症介质血液水平的变化（可能导致癌症发展增加）对于结肠癌预防目标至关重要。了解结肠癌风险较低的生物标志物个体的变化也可能导致风险分析，特定目标识别和预防策略。

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.