Vitamin D & Calcium Regulation Biomarkers in Colon Cancer Risk Reduction

描述（由申请人提供）：本提案的长期目标是更好地了解钙和维生素D如何影响结直肠癌发生。流行病学研究普遍支持钙，维生素D和结直肠癌风险之间的负相关，尽管研究结果不一致。在腺瘤性息肉复发的干预性研究中，饮食因素中，钙能最稳定地降低风险。最近的证据进一步支持钙和维生素D的相互作用或相加作用。两个有趣的机制假说涉及维生素D自分泌/旁分泌活性和组织特异性钙敏感受体（CaSR）。钙和维生素D在体外和体内表现出抗增殖和促分化作用。维生素D的活性形式1，25（OH）2D是维生素D受体（VDR）的天然配体，其调节参与细胞周期控制的许多基因的表达。经典的1，25（OH）2D合成被认为仅受肾脏中1，α（OH）酶（CYP 27 B1）对25（OH）D（维生素D的储存形式）的作用调节。然而，现在还已知1，25（OH）2D在结肠组织中直接合成和降解，不依赖于肾1，25（OH）2D合成的通常触发因素。关于启动组织特异性1，25（OH）2D合成（通过CYP 27 B1）和catalysts（通过CYP 24）的因子知之甚少。钙敏感受体（CaSR）被1，25（OH）2D上调，并且也被认为调节上皮分化。VDR表达受多种因素影响，可能影响钙和维生素D的预防效果。维生素D代谢酶或CaSR在结肠组织中的表达是否响应于血浆维生素D浓度、饮食或非饮食因素，以及维生素D或钙对结肠的影响是否通过VDR表达而改变，是当前感兴趣的。本研究使用了一项正在进行的随机、双盲、安慰剂对照的2x2析因初步试验（n=88）中收集的数据和生物样本（正常外观的结直肠组织的血液和活检），该试验旨在研究钙和维生素D对散发性结直肠腺瘤患者结直肠癌风险生物标志物的调节作用。使用自动定量免疫组织化学和图像分析，我们将测量CYP 27 B1和CYP 24羟化酶的表达（分别作为组织特异性1，25（OH）2D合成和降解的测量）、CaSR和VDR，以研究钙或维生素D补充剂、血液中的维生素D代谢物、或其他饮食和生活方式因素影响其表达。本初步研究将提供把握度计算所需的变异性估计值，以将这些研究问题应用于更大规模的正在进行的干预试验。这项研究的结果需要进一步开发维生素D，钙和相关药物来预防结直肠癌，这是美国癌症死亡的第二大原因。

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to better understand how calcium and vitamin D influence colorectal carcinogenesis. Epidemiological studies have generally supported an inverse association between calcium, vitamin D and risk of colorectal cancer, although findings have been inconsistent. Of dietary factors tested in intervention studies of adenomatous polyp recurrence, calcium has most consistently reduced risk. Recent evidence further supports either an interactive or additive role of calcium and vitamin D. Two intriguing mechanistic hypotheses concern vitamin D autocrine/paracrine activity and tissue-specific calcium sensing receptors (CaSR). Calcium and vitamin D exhibit anti-proliferative and pro-differentiation effects in vitro and in vivo. The active form of vitamin D, 1,25(OH)2D, is the natural ligand for the vitamin D receptor (VDR), which regulates expression of numerous genes involved in cell cycle control. Classically 1,25(OH)2D synthesis has been thought to be solely regulated by the action of 1,alpha(OH)ase (CYP27B1) on 25(OH)D (storage form of vitamin D) in the kidney. However, 1,25(OH)2D is now also known to be directly synthesized and degraded in colon tissue, independent of usual triggers of renal 1,25(OH)2D synthesis. Remarkably little is known about the factors that initiate tissue-specific 1,25(OH)2D synthesis (by CYP27B1) and catabolism (by CYP24). The calcium sensing receptor (CaSR) is upregulated by 1,25(OH)2D and is also thought to regulate epithelial differentiation. VDR expression, which is influenced by multiple factors, may modify the preventive efficacy of calcium and vitamin D. Whether expression of vitamin D metabolizing enzymes or CaSR in colon tissue responds to plasma vitamin D concentrations, diet, or non-dietary factors, and whether the effects of vitamin D or calcium on the colon is modified by VDR expression, is of current interest. This study uses data and biological samples (blood and biopsies of normal-appearing colorectal tissue) collected in an ongoing, randomized, double-blind, placebo-controlled 2x2 factorial pilot trial (n=88) of calcium and vitamin D in the modulation of biomarkers of risk for colorectal cancer in sporadic colorectal adenoma patients. Using automated quantitative immunohistochemistry with image analysis, we will measure the expression of CYP27B1 and CYP24 hydroxylases (as measures of tissue-specific 1,25(OH)2D synthesis and degradation, respectively), the CaSR, and the VDR in the normal-appearing colorectal epithelium to investigate whether calcium or vitamin D supplementation, vitamin D metabolites in the blood, or other diet and lifestyle factors influence their expression. This pilot study will provide the estimates of variability required for power calculations to apply these research questions to a larger, ongoing, intervention trial. The results of this study are needed for further progress in developing vitamin D, calcium and related agents in preventing colorectal cancer, the second leading cause of cancer deaths in the US.