Role of Kupffer Cell in Hepatic Carcinogenesis

描述（由申请人提供）：肝癌目前在所有人类癌症中发病率排名第五，癌症死亡率排名第三。最近的调查报告显示，肝癌在美国的发病率急剧上升。人类肝癌的病因与许多因素有关，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。慢性肝脏增生是人类肝脏肿瘤发展的共同特征，因此似乎遵循与啮齿动物肝脏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，非实质细胞，包括库普弗细胞（常驻肝巨噬细胞），可能是肝脏生长调节的重要组成部分。激活后的Kupffer细胞可以产生一系列产物，包括活性氧中间体和细胞因子，这些产物可能影响细胞生长调节。对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这一过程中所起的作用。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，Kupffer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了初始细胞的细胞增殖，最终导致肝肿瘤的发生。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。肿瘤启动子激活的库普弗细胞的产物将被确定并检查潜在的肝细胞生长调节作用。此外，我们还将研究LPS（脂多糖）或肝脏肿瘤促进剂对瘤前病变生长和正常肝脏生长的库普弗激活作用。这些研究将为肝癌发生肿瘤促进阶段库普弗细胞和肝细胞之间的相互作用提供信息。这些研究将进一步加深我们对人类肝癌发生发展机制的认识，并在预防和治疗方面具有潜在的应用价值。

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.