Microvasculature in Colon Field Carcinogenesis: Clinical-Biological Implications

项目摘要 该项目的总体目标是开发一种直肠探头，用于最小侵入性高度准确的危险分层 其愿景是将其用于结肠癌筛查的精确医学方法， 化学预防（伴随生物标志物）。我们将采用尖端的生物光子学（ISOCT）和生物 结合大规模人体研究的方法，以阐明粘膜的临床/生物学意义， 早期血供增加（EIBS）。我们的多学科小组在两个方面广泛报道了EIBS 动物模型和人类研究（n>1000）通过尖端生物光子技术的发展 即偏振选通光谱（PGS）和最近的逆光谱光学相干 断层扫描（ISOCT）。在临床上，直肠EIBS对晚期腺瘤有很好的诊断作用（AUC >0.8）， 受到种族和性别的影响。从生物学上讲，我们关于早期结肠粘膜代谢的数据 在动物模型和人类中的重编程（瓦尔堡样效应）提供了一种潜在的机制， EIBS。对于因果关系的见解，试点动物研究表明，靶向微循环与 血管紧张素受体阻断剂氯沙坦降低EIBS，同时抑制结肠肿瘤发生。 此外，化学预防剂似乎可以逆转癌前结肠组织中的Warburg样生理学， 粘膜我们假设EIBS是代谢重编程的一种表现， ISOCT前所未有的精确度。在目标1（技术）中，我们将开发和验证ISOCT光纤 探讨并确定其对血红蛋白浓度、氧合状态和血管的准确性 不同浅表组织深度处的直径。在目标2（生物标志物）中，我们将开发和验证直肠EIBS 使用针对性别和种族优化的预测规则预测晚期腺瘤的存在 与血红蛋白氧合、深度和血管半径和密度相关的生物标志物，旨在提高灵敏度 特异性≥ 90%。对于代谢生理相关性，我们将询问短期原发性结肠活检 细胞培养物通过细胞外通量分析（Seahorse）作为瓦尔堡的生理标记。我们将相互关联 与ISOCT读数和肿瘤存在（种族/性别特异性）以及基因表达一起沿着 和瓦尔堡有牵连在目标3（因果洞察力）中，我们将进行动物研究，以确定是否 使用氯沙坦（血管紧张素2抑制剂）和二甲双胍靶向EIBS和次级代谢事件 （已知有希望逆转瓦尔堡效应的化学预防剂）将是一种潜在的腺瘤预防剂 战略生物学上，这项研究将提供明确的证实，EIBS是一个重要的效应代谢 结肠癌发生中的重编程。临床上，直肠EIBS的侵入性最小， 在初级保健环境中使用，以确定是否需要结肠镜检查，并滴定或停止 化学预防剂，以避免暴露于不能获得治疗益处的患者。 这些药物的成本/毒性。这种新的模式可能预示着CRC预防的精准医学时代。

Project Summary The overall goal of this project is to develop a rectal probe for minimally intrusive highly accurate risk stratification with the vision of utilizing it for a precision medicine approach to colon cancer screening and also potentially chemoprevention (companion biomarker). We will employ cutting edge biophotonics (ISOCT) and biological approaches combined with large scale human studies to elucidate the clinical/biological implications of mucosal early increase in blood supply (EIBS). Our multi-disciplinary group has extensively reported on EIBS in two animal models and human studies (n>1000) through the development of cutting-edge biophotonics technology namely the polarization gated spectroscopy (PGS) and more recently inverse spectroscopic optical coherence tomography (ISOCT). Clinically, rectal EIBS had excellent diagnostics of advanced adenomas (AUC >0.8) albeit impacted somewhat by race and gender. Biologically, our data on early colonic mucosal metabolic reprogramming (Warburg like effect) in both animal models and humans provides a potential mechanism for EIBS. For Causational Insights, pilot animal studies demonstrated that targeting microcirculation with the angiotensin receptor blocker losartan decreased EIBS with a concomitant suppression of colonic tumorigenesis. Furthermore, chemopreventive agents appear to reverse the Warburg-like physiology in the premalignant colonic mucosa. We hypothesize that EIBS is a manifestation of metabolic reprogramming that can be detectable with unprecedented accuracy with ISOCT. In aim 1 (technology), we will develop and validate the ISOCT fiberoptic probe and ascertain its accuracy for determining hemoglobin concentration, oxygenation status and blood vessel diameter at various superficial tissue depths. In aim 2 (biomarker), we will develop and validate a rectal EIBS prediction rule for the presence of advanced adenomas with prediction rule optimized for gender & race using biomarkers related to hemoglobin oxygenation, depth and blood vessel radius and density aiming for sensitivity & specificity ≥90%. For metabolic physiological correlates, we will interrogate the short term primary colon biopsy cell cultures via the extracellular flux analysis (Seahorse) as a physiological marker of Warburg. We will correlate with ISOCT readings and neoplasia presence (race/gender specific) along with the expressions of genes implicated in Warburg. In aim 3 (causational insight), we will perform animal studies to determine whether targeting the EIBS and secondary metabolic events using losartan (angiotensin 2 inhibitor) and metformin (promising chemopreventive agent known to reverse Warburg effects) would be a potential adenoma prevention strategy. Biologically, this study will provide definitive confirmation that EIBS is an important effector of metabolic reprogramming in colon carcinogenesis. Clinically, a rectal EIBS would be minimally intrusive and could be employed in the primary care setting to determine need for colonoscopy and also titrate or discontinue chemopreventive agents in order not to expose patients who do not derive a therapeutic benefit to the cost/toxicity of these agents. This new paradigm may herald the era of precision medicine in CRC prevention.