Curcumin and Quercetin in Colon Cancer: Role of Macrophage-Induced Inflammation

描述（由申请人提供）：结直肠癌（CRC）是美国癌症死亡的第二大原因，也是第四大最常诊断的癌症。越来越多的人认识到，饮食诱导的炎症反应调节是人类癌变过程的核心。这一论点源于对促炎状态与肿瘤促进密切相关的观察。食用抗炎膳食成分姜黄素（姜黄素是印度香料咖喱的一种成分）和槲皮素（一种存在于各种水果和蔬菜中的类黄酮）与降低结直肠癌风险有关。众所周知，长期使用这些饮食成分比抗炎药物具有更大的安全范围，这使得它们更有可能帮助预防癌症。虽然许多研究已经检测了膳食补充剂对癌症炎症的影响，但没有一个研究专门检测了组织巨噬细胞（Ms），炎症的主要介质，在这些影响中的作用。此外，很少有人研究膳食补充剂对致癌生物学机制的影响。本项目的总体目标是：1)确定抗炎饮食成分姜黄素和槲皮素对结直肠癌进展的独立和联合作用；2)确定这些益处是否来自m诱导炎症的减少。显然，m诱导的炎症在结直肠癌的发生和发展中起着重要作用，它也可能导致各种疾病行为，如疲劳、食欲不振、身体消瘦，这些疾病行为会大大降低结直肠癌患者的生活质量。相当大比例，也许是大多数的crc与非遗传因素有关，如营养不足和/或营养过剩，这可以通过多种方式放大炎症。抗炎膳食成分姜黄素和槲皮素的独立、附加或协同作用可能对预防结直肠癌具有重要的公共卫生意义。本项目的具体目的是：1)阐明姜黄素和槲皮素对M浸润、炎症、CRC进展和宿主存活的联合作用；2)更具体地确定M诱导的炎症在这些作用中的作用。我们将利用小鼠转基因结直肠癌模型来确定姜黄素和槲皮素在结直肠癌特定阶段（如预防与治疗）对炎症过程、M浸润、肿瘤进展和宿主生存的独立和联合作用。此外，我们将使用M操作技术来评估M是否是姜黄素和槲皮素对炎症、肿瘤进展和宿主生存影响的重要共同途径。该项目的总体目标是开发一种临床可测试的方案，以延缓和/或预防结直肠癌，并开始了解其作用机制是否与M浸润和随后的炎症有关，这些炎症可以通过进一步的行为和/或医学治疗来针对。公共卫生相关性：膳食化合物姜黄素（印度香料咖喱的一种成分）和槲皮素（一些水果和蔬菜的一种成分）具有抗炎特性，与降低结肠癌风险有关。这些化合物改变炎症过程，这可能与肿瘤的形成和发展有关。拟议研究的目的是调查姜黄素和槲皮素对结肠癌进展的独立和联合作用，并确定这些作用是否源于巨噬细胞诱导炎症的减少。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer death in the United States and the fourth most commonly diagnosed cancer. There is increasing recognition of diet-induced modulation of inflammatory responses as being central to the processes of human carcinogenesis. The argument for this stems from the observations that pro-inflammatory states are closely linked to tumor promotion. The consumption of the anti- inflammatory dietary constituents curcumin, which is a component of the Indian spice currie, and quercetin, a flavonoid present in various fruits and vegetables, have been associated with reduced CRC risk. Such components of diet are generally known to have a much wider safety margin with chronic use than are anti- inflammatory drugs, which make them more viable candidates to aid in cancer prevention. While a number of studies have examined the effects of dietary supplements on inflammation in cancer, none have specifically examined the role of tissue macrophages (Ms), primary mediators of inflammation, on these effects. Further, few have examined combinations of dietary supplements on the biological mechanisms of carcinogenesis. The overarching goal of this proposed project is to 1) determine the independent and combined effects of the anti-inflammatory dietary constituents curcumin and quercetin on CRC progression, and 2) to determine whether these benefits result from a reduction in M-induced inflammation. It is clear that M-induced inflammation plays an important part in the initiation and progression of CRC, and it may also be responsible for various sickness behaviors like fatigue, lack of appetite, and body wasting that can drastically decrease quality of life in CRC patients. A substantial proportion and perhaps the majority of CRCs are associated with non-genetic factors, such as inadequate and/or over nutrition, which can amplify inflammation in a number of ways. An independent, additive or synergistic effect of the anti-inflammatory dietary constituents curcumin and quercetin may be of critical public health significance in the prevention of CRC. The specific aims of this project are to 1) to elucidate the combined effects of curcumin and quercetin on M infiltration, inflammation, CRC progression and host survival and 2) to more specifically determine the role of M-induced inflammation on these effects. A mouse transgenic model of CRC will be used to determine the independent and combined effects of curcumin and quercetin on inflammatory processes, M infiltration, tumor progression and host survival at specific stages of CRC (e.g. prevention versus treatment). Furthermore, we will use M manipulation techniques to evaluate whether Ms are an important common pathway of the effects of curcumin and quercetin on inflammation, tumor progression and host survival. The overall goal of this project is to develop a clinically testable regimen to delay and/or prevent CRC and to begin to understand if the mechanisms of the effects are related to M infiltration and subsequent inflammation that could be targeted by further behavioral and or medical treatment. PUBLIC HEALTH RELEVANCE: The dietary compounds curcumin, a component of the Indian spice curry, and quercetin, a component of some fruits and vegetables, have anti-inflammatory properties and have been associated with reduced colon cancer risk. These compounds modify inflammatory processes which may be linked with the formation and development of tumors. The goal of the proposed study is to investigate the independent and combined effects of curcumin and quercetin on the progression of colon cancer and to determine if these effects result from a reduction in macrophage-induced inflammation.