role of adipokines in colon epithelial cell homeostasis

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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. Leptin, interleukin-6 (IL-6) and adiponectin are three such adipokines that may a play direct role in obesity- associated cancer progression. 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. Inflammation-associated colon cancer is a well known clinical phenomenon in inflammatory bowel disease where inflammatory stimuli promote survival and proliferation of initiated neoplastic cells. We hypothesize that an imbalance in adipokines is a key inflammatory promotional signal for preneoplastic cells. There is strong biological plausibility, supported by epidemiologic evidence, that an imbalance in adipokines is causally related to obesity-associated colon cancer. However, the mechanism is not understood. A critical gap exists in our mechanistic understanding of the correlation between obesity and colon cancer risk. As such, the long-term goal of this research is to understand how obesity-associated systemic elevation of adipokines increases colon cancer risk. Understanding these early signals will lead to cancer prevention targets for obesity-associated colon cancer risk. This application investigates the differential cell signaling and proteinase mechanisms activated by leptin in preneoplastic but not normal colon epithelial cells through preclinical modeling. The neoplastic transformation of colon cancer is well characterized. We will utilize normal and preneoplastic colonic epithelial cells consistent with the transformation paradigm to address the central hypothesis of this application in two specific aims; 1) identify differential transcription factors that are causally responsible for leptin-induced (and adiponectin blocked) IL-6 signaling proliferation in preneoplastic colon epithelial cells 2) identify proteinases responsible for leptin-induced differential shedding of the soluble interleukin-6 receptor between preneoplastic and normal colonic epithelial cells. It is anticipated that upon identification of this biological mechanism of obesity-induced colon cancer promotion, it may become possible to target this mechanism. The research in this application is relevant to public health because it is critical to colon cancer prevention targets to understand how elevated blood levels of obesity-associated factors may lead to the development of cancer. As an outcome of these studies, it is also possible that a novel mechanism identified by this research may lead to the development of potential therapeutic targets to aid in preventing and/or treating obesity-associated colon cancer risk.