This is a Bioengineering Research Grant (BRG) application. Targeting patients at highest risk for colorectal cancer is critical in designing effective anticancer strategies. Many risk-stratification techniques exploit the """"""""field effect"""""""", the proposition that the genetic/environmental milieu that results in a neoplastic lesion in one area of the colon should be detectable throughout the colon. Unfortunately, the most widely used marker of the field effect, the distal adenomatous polyp, is plagued by suboptimal sensitivity and poor positive predictive value. Therefore, development of accurate techniques to detect the field effect is of paramount importance. Our team of biomedical engineers, gastroenterologists, and cancer biologists has recently developed four-dimensional elastic light scattering fingerprinting (4D-ELF) to quantify tissue microarchitecture and microvasulature. In our studies with animal models of experimental colon carcinogenesis (the azoxymethane-treated rat and the MIN-mouse) we observed, for the first time, a profound early increase in subepithelial blood supply (EIBS) at a time point that precedes the formation of adenomas as well as any other conventional histological or molecular markers of colon cancer. Moreover, the performance of EIBS as a marker of predisposition for colon neoplasia dramatically exceeded any previously described biomarkers, with high sensitivity, specificity, negative and positive predictive values. We also confirmed this phenomenon in humans in our pilot human studies. Although it has been previously established that later-stage (e.g. adenoma-carcinoma) neoplastic lesions have increased blood supply, ours were the first data to show EIBS in early preadenomatous stages of colon carcinogenesis. Based on these preliminary data, we hypothesize that EIBS can serve as an accurate early biomarker for colon carcinogenesis. We propose to (1) develop and validate a 4D-ELF-based optical spectroscopic instrument for assessment of the blood supply to colonic epithelium in ex vivo tissues, and (2) using this instrument, evaluate EIBS as an intermediate biomarker for experimental and human colon carcinogenesis in order to insure that this effect is not mode-specific and to confirm its relevance to human sporadic colon carcinogenesis. The successful outcome of this study may lead to a wide range of future investigations including the assessment of EIBS as a screening tool for colon cancer, assessment of the molecular mechanisms for EIBS and development of anti-EIBS strategies, and utilization of our innovative optical spectroscopy technique for blood supply quantitation for variety applications.
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