Dietary Marine Algae Extract and Colon Cancer Chemoprevention

描述（由申请人提供）：这里提出的研究将检验一种红藻提取物抑制异常结肠上皮细胞生长的能力。萃取物的来源是北大西洋红藻，石藻。这种提取物富含Ca2+，但也含有可检测到的大约70种其他矿物质。本研究将探讨两个关键问题。首先，在一项为期15个月的饮食研究中，在高脂肪西式饮食中使用基因“正常”的小鼠，海藻提取物是否显示出对结肠增生、结肠息肉和结肠癌的疗效，并且提取物是否比无机Ca2+单独更有效？其次，细胞外钙感应受体（CaSR）是藻类提取物化学预防作用的关键靶点吗？为了解决第一个问题，野生型（C57bl/6）小鼠将在高脂肪饮食中维持15个月，这种饮食已知会导致多发性结肠息肉的发展，在一些小鼠中，还会导致结肠癌（Nemark饮食）。一些高脂肪饮食的老鼠也会接受藻类提取物。作为对照，其他小鼠喂食添加无机Ca2+（碳酸钙）的高脂肪饲料。提出的研究所基于的假设是，藻类提取物将提供比无机Ca2+单独更有效的结肠化学预防。为了解决第二个问题，我们将评估在存在或不存在藻类提取物的情况下维持的一系列人类结肠癌细胞系中CaSR的表达。已知一些细胞系单独对细胞外Ca2+的反应有缺陷。我们将比较Ca2+响应和非响应细胞对海藻提取物的生长停滞和分化。在其他实验中，我们将使用siRNA方法下调结肠癌细胞系中的CaSR表达，并确定CaSR表达是否对藻类提取物介导的生长抑制至关重要。这些实验的结果将为藻类提取物对结肠癌化学预防的细胞和分子基础提供见解，并将为后续的临床研究提供指导（如果有必要的话）。公共卫生相关性：本申请中提出的研究的总体目标是确定一种含有多达70种不同矿物质的红藻提取物是否有能力抑制高脂肪西式饮食小鼠的异常结肠上皮细胞生长，确定含有高矿物质的藻类提取物是否比单独使用钙更有效，并确定钙敏感受体是否是藻类提取物生长调节活动的关键目标。

DESCRIPTION (provided by applicant): The studies proposed here will examine a red marine algae extract for ability to inhibit the outgrowth of abnormal colonic epithelial cells. The source of the extract is the North Atlantic red algae, Lithothamnium coralliodides. The extract is rich in Ca2+ but also contains detectable levels of approximately 70 other minerals. Two pivitol questions will be addressed in this study. First, does the marine algae extract demonstrate efficacy against colonic hyperplasia, colonic polyps and colon carcinoma when used in a 15-month dietary study with genetcally "normal" mice on a high-fat Western stye diet, and is the extract more effective than inorganic Ca2+ alone? Second, is the extracellular calcium-sensing receptor (CaSR) the critical target for the chemopreventive effects of the algae extract? To address the first question, wild-type (C57bl/6) mice will be maintained for 15 months on a high fat diet that is known to result in the development of multiple colonic polyps and, in some mice, colon cancer (Nemark diet). Some mice on the high fat diet will also receive the algae extract. As controls, other mice will be fed the high fat diet supplemented with inorganic Ca2+ (calcium carbonate). The hypothesis on which the proposed studies are based is that the algae extract will provide more effective colon chemoprevention than inorganic Ca2+ alone. To address the second question, we will assess expression of CaSR in a series of human colon cancer cell lines maintained in the presence or absence of the algae extract. Some of the lines are known to be defective in their response to extracellular Ca2+ alone. We will compare growth arrest and differentiation of the Ca2+ - responsive and non-responsive cells to the marine algae extract. In additional experiments, we will use an siRNA approach to down-regulate CaSR expression in the colon cancer cell lines and determine if CaSR expression is critical for growth inhibition mediated by the algae extract. The results of these experiments will provide insight into cellular and molecular basis of colon cancer chemoprevention by the algae extract and will provide direction for subsequent clinical studies (if warranted). PUBLIC HEALTH RELEVANCE: The overall goals of the studies proposed in this application are to determine if a red marine algae extract that contains detectable levels of up to 70 different minerals has the capacity to suppress abnormal colon epithelial cell growth in mice on a high-fat, Western-style diet, do determine if the high-mineral - containing algae extract is more effective than calcium alone and to determine if the calcium-sensing receptor is the critical target for the growth modulating activities of the algae extract.