Role of Kupffer Cell in Hepatic Carcinogenesis

库普弗细胞在肝癌发生中的作用

• 批准号: 7175310
• 负责人: JAMES E KLAUNIG
• 金额: $ 22.7万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175310
• 关键词: Address; Africa; Apoptosis; Carcinogens; Cell Line; Cell Proliferation; Cells; Chemicals; Chronic; Class; Clonal Expansion; Coupled; Cultured Cells; DNA biosynthesis; DNA chemical synthesis; Development; Diagnostic Neoplasm Staging; Dichloromethylene Diphosphonate; Diethylnitrosamine; End Point; Etiology; Europe; Event; Gene Mutation; Growth; Hepatic; Hepatitis B; Hepatocarcinogenesis; Hepatocyte; Human; Human Development; In Vitro; Incidence; Incubated; Infection; Inflammation; Investigation; Iron Overload; Knock-out; Knockout Mice; Kupffer Cells; Laboratories; Lesion; Link; Lipopolysaccharides; Liposomes; Literature; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Methods; Mouse Strains; Mus; Mutate; Mycotoxins; NADPH Oxidase; Neoplasms; Numbers; Peroxisome Proliferators; Play; Prevention therapy; Principal Investigator; Process; Production; Protocols documentation; Reactive Oxygen Species; Regulation; Reporting; Research Personnel; Rodent; Rodent Model; Role; Signaling Molecule; Southeastern Asia; Staging; Standards of Weights and Measures; Subgroup; Tumor Promoters; Tumor Promotion; Work; carcinogenesis; cell growth; cell growth regulation; cell injury; cell type; chemical group; cytokine; environmental agent; in vivo; knockout animal; liver cell proliferation; liver hyperplasia; macrophage; male; mortality; programs; promoter; reactive oxygen intermediate; release factor; response; tumor; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Liver cancer currently ranks fifth highest of all human cancers in incidence and third highest in cancer mortality. Recent investigations have reported a dramatic increase in the incidence of the liver cancer in the US. The etiology of human liver cancer has been linked to a number of factors including hepatitis B and C infection, mycotoxin exposure, iron overload, and environmental agents. Chronic liver hyperplasia is a common feature in human liver neoplasia development and as such appears to follow the same sequential multi-step process seen in rodent liver. While the hepatocyte is the target of most liver carcinogens, recent evidence suggests that non-parenchymal cells, including the Kupffer cell (the resident liver macrophage), may be an important component of growth regulation in the liver. The Kupffer cell upon activation can produce an array of products, including reactive oxygen intermediates and cytokines, which may impact on cell growth regulation. Little is known about the role of the Kupffer cell in hepatocarcinogenesis. The long term objectives of these studies therefore are to better understand the role that the Kupffer cell plays in this process. The proposed studies will specifically examine whether activation of the Kupffer cell is important in the tumor promotion stage of hepatic tumorigenesis. The overall hypothesis of these studies is that activation of Kupffer cells result in the release of cellular growth regulatory signaling molecules that selectively produce an increase in cell proliferation in initiated cells ultimately leading to hepatic neoplasia. These studies will examine the effect of Kupffer cell activation and deactivation on both normal (noninitiated) and initiated hepatocyte growth, and will determine whether activation hepatic tumor promoting compounds activate Kupffer cells, which result in hepatocyte proliferation. The products of the tumor promoter activated Kupffer cells will be determined and examined for potential hepatocyte growth regulatory effects. In addition, the effect of Kupffer activation, either by LPS (lipopolysaccharide) or hepatic tumors promoters on preneoplastic lesion growth and normal liver growth will be investigated These studies will provide information regarding the interplay between the Kupffer cell and heptatocytes during the tumor promotion stage of hepatocarcinogenesis. These studies will further our understanding into the mechanisms of the development and progression of human liver cancer with potential application to prevention and therapy.

描述（由申请人提供）：目前，肝癌的发病率在所有人类癌症中排名第五，在癌症死亡率中排名第三。最近的调查报告显示，美国肝癌的发病率急剧上升。人类肝癌的病因与多种因素有关，包括乙型和丙型肝炎感染、霉菌毒素暴露、铁超载和环境因素。慢性肝增生是人类肝脏肿瘤发展的一个常见特征，因此似乎遵循啮齿动物肝脏中所见的相同的顺序多步骤过程。虽然肝细胞是大多数肝脏致癌物的目标，但最近的证据表明，包括库普弗细胞（肝脏巨噬细胞）在内的非实质细胞可能是肝脏生长调节的重要组成部分。库普弗细胞激活后可以产生一系列产物，包括活性氧中间体和细胞因子，这可能会影响细胞生长调节。关于库普弗细胞在肝癌发生中的作用知之甚少。因此，这些研究的长期目标是更好地了解库普弗细胞在此过程中发挥的作用。拟议的研究将专门研究库普弗细胞的激活在肝肿瘤发生的肿瘤促进阶段是否重要。这些研究的总体假设是库普弗细胞的激活导致细胞生长调节信号分子的释放，这些信号分子选择性地增加起始细胞的细胞增殖，最终导致肝肿瘤。这些研究将检查库普弗细胞激活和失活对正常（非启动）和启动肝细胞生长的影响，并将确定激活肝肿瘤促进化合物是否激活库普弗细胞，从而导致肝细胞增殖。将测定肿瘤启动子激活的库普弗细胞的产物并检查其潜在的肝细胞生长调节作用。此外，还将研究LPS（脂多糖）或肝脏肿瘤促进剂激活库普弗细胞对癌前病变生长和正常肝脏生长的影响。这些研究将提供有关肝癌发生的肿瘤促进阶段库普弗细胞和肝细胞之间相互作用的信息。这些研究将进一步加深我们对人类肝癌发生和进展机制的理解，并有可能应用于预防和治疗。