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。最近的调查报告了美国肝癌发病率的急剧增加。人类肝癌的病因学与许多因素有关，包括B和C型肝炎感染、霉菌毒素暴露、铁过载和环境因子。慢性肝脏增生是人类肝脏肿瘤发展的常见特征，因此似乎遵循啮齿动物肝脏中观察到的相同顺序多步骤过程。虽然肝细胞是大多数肝脏致癌物的靶点，但最近的证据表明，非实质细胞，包括枯否细胞（常驻肝脏巨噬细胞），可能是肝脏生长调节的重要组成部分。库普弗细胞在活化后可产生一系列产物，包括活性氧中间体和细胞因子，其可影响细胞生长调节。关于枯否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枯否细胞在这一过程中发挥的作用。拟议的研究将专门检查枯否细胞的激活是否在肝肿瘤发生的肿瘤促进阶段很重要。这些研究的总体假设是枯否细胞的活化导致细胞生长调节信号分子的释放，这些分子选择性地在起始细胞中产生细胞增殖的增加，最终导致肝肿瘤形成。这些研究将检查枯否细胞活化和失活对正常（非起始）和起始肝细胞生长的影响，并将确定活化肝肿瘤促进化合物是否活化枯否细胞，从而导致肝细胞增殖。将测定并检查肿瘤促进剂活化枯否细胞的产物的潜在肝细胞生长调节作用。此外，Kupffer激活的影响，无论是由LPS（脂多糖）或肝肿瘤的促进剂对癌前病变的生长和正常的肝脏生长将进行调查。这些研究将提供信息之间的相互作用Kupffer细胞和肝细胞在肝癌的肿瘤促进阶段。这些研究将进一步加深我们对人类肝癌发生和发展机制的理解，并可能应用于预防和治疗。

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.