ErbB Receptor Signaling in DEN-induced Murine Hepatocarcinogenesis

DEN 诱导的小鼠肝癌发生中的 ErbB 受体信号转导

基本信息

批准号：
8043654
负责人：
WILLIAM E RUSSELL
金额：
$ 16.43万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8043654
关键词：
Alleles Animal Model Animals Cancer Etiology Cessation of life Chemoprevention Chemopreventive Agent Cirrhosis Clinical Complex Data Development Diethylnitrosamine Differentiation and Growth Disease EGF gene Epidermal Growth Factor Epidermal Growth Factor Receptor Erlotinib Etiology Family member Funding Opportunities Gefitinib Genes Genetic Genetic Models Goals Grant Hepatic Hepatitis Hepatocarcinogenesis Hepatocyte Homo Homologous Gene Human Incidence Individual Injury Intervention Investigation Knock-out Knockout Mice Laboratories Ligands Liver Liver Regeneration Malignant Neoplasms Malignant neoplasm of liver Mediator of activation protein Modeling Molecular Target Mus National Cancer Institute Pathway interactions Patients Pattern Play Prevention Primary carcinoma of the liver cells Protein Family Protein Tyrosine Kinase Proteins Rattus Receptor Protein-Tyrosine Kinases Receptor Signaling Reporting Rodent Rodent Model Role Secondary Prevention Signal Transduction Therapeutic Tyrosine Kinase Inhibitor United States angiogenesis cancer cell cancer type chemotherapy cyclooxygenase 2 erbB Genes improved inhibitor/antagonist interest meetings mouse development novel prevent public health relevance receptor response small molecule

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Among the most profound consequences of disordered hepatocellular growth and differentiation is the development of hepatocellular carcinoma (HCC). HCC is the fifth most common cancer and the third leading cause of cancer deaths worldwide, resulting in over 1 million deaths per year. Its incidence is rising, particularly in the United States, where it has increased by 70% over the last 25 years. No effective secondary prevention or systemic treatments are available. We have a longstanding interest in the role of epidermal growth factor (EGF and its homologs), and the ErbB tyrosine kinase receptors (including the EGF receptor, EGFr) in the control of hepatocellular growth and differentiation. Gefitinib, a small molecule inhibitor of the EGFr tyrosine kinase, will reduce the development of HCC in rats exposed to N- nitrosodiethylamine (DEN), which induces liver injury, cirrhosis, and ultimately HCC. Gefitinib and other EGFr tyrosine kinase inhibitors have recently shown promise in the treatment of human HCC, indicating an important role for the ErbB proteins in hepatocellular carcinogenesis and the relevance of animal models for human HCC. We have shown that only three ErbB proteins are expressed in liver under normal circumstances (EGFr, ErbB2 and ErbB3), and that there is a developmentally-regulated pattern in their expression by hepatocytes. Although they are frequently studied in isolation, the ErbB proteins are highly interactive and form signaling homo- and heterodimers. In human HCC, ErbB3 is one of 217 proteins (out of 9000 examined) that is consistently upregulated; either EGFr or ErbB2 (but not both) tend to be upregulated along with ErbB3. The hypothesis under investigation is that ErbB tyrosine kinases are critical to development of HCC in the DEN rodent model. We propose a systematic study of the consequences of genetic deletion of these molecules in hepatocytes in order to assess their importance in the initiation and progression of HCC. We have generated hepatocyte-specific single and double gene ErbB knockout mice. These animals develop normally and are ideal genetic models to analyze the progression from hepatitis to cirrhosis to hepatocellular carcinoma (HCC) in the setting of ErbB loss. We also have access to a mouse bearing a hypermorphic allele of the EGFr, dsk5, that signals more robustly in response to ligand activation. We expect to identify the specific ErbB receptors and downstream pathways involved in liver carcinogenesis. These studies should assist in the development of molecular targets for interventions to prevent or treat HCC in humans. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma (HCC), or liver cell cancer, is the fifth most common cancer, and is the third leading cause of cancer death; the incidence of HCC has risen by over 70% over the past 25 years in the United States. There is significant evidence that a family of proteins called the ErbB tyrosine kinases play a role in the development of liver cancer; they would be extremely good targets for the control of HCC. Using genetically altered mice in which the hepatic ErbB proteins have been rendered nonfunctional or hyperfunctional, we expect to identify key targets for the development of novel chemotherapy to treat HCC.

描述（由申请人提供）：我们实验室的长期目标是了解控制肝脏生长、分化和再生的机制。肝细胞生长和分化紊乱最严重的后果之一是肝细胞癌（HCC）的发展。 HCC 是全球第五大常见癌症，也是全球第三大癌症死亡原因，每年导致超过 100 万人死亡。其发病率正在上升，特别是在美国，在过去 25 年里增加了 70%。没有有效的二级预防或系统治疗。我们长期以来对表皮生长因子（EGF 及其同系物）和 ErbB 酪氨酸激酶受体（包括 EGF 受体 EGFr）在控制肝细胞生长和分化中的作用感兴趣。吉非替尼是一种 EGFr 酪氨酸激酶的小分子抑制剂，可减少暴露于 N-亚硝基二乙胺 (DEN) 的大鼠的 HCC 发展，DEN 会诱发肝损伤、肝硬化，并最终导致 HCC。吉非替尼和其他 EGFr 酪氨酸激酶抑制剂最近在人类 HCC 的治疗中显示出前景，表明 ErbB 蛋白在肝细胞癌发生中的重要作用以及人类 HCC 动物模型的相关性。我们已经证明，正常情况下肝脏中仅表达三种 ErbB 蛋白（EGFr、ErbB2 和 ErbB3），并且肝细胞的表达存在发育调节模式。尽管经常单独研究 ErbB 蛋白，但它们具有高度相互作用并形成信号同源二聚体和异源二聚体。在人类 HCC 中，ErbB3 是持续上调的 217 种蛋白质之一（在检查的 9000 种蛋白质中）； EGFr 或 ErbB2（但不是两者）往往会与 ErbB3 一起上调。正在研究的假设是 ErbB 酪氨酸激酶对于 DEN 啮齿动物模型中 HCC 的发展至关重要。我们建议对肝细胞中这些分子基因缺失的后果进行系统研究，以评估它们在 HCC 发生和进展中的重要性。我们已经培育出肝细胞特异性单基因和双基因 ErbB 敲除小鼠。这些动物发育正常，是分析 ErbB 缺失情况下从肝炎到肝硬化再到肝细胞癌 (HCC) 进展的理想遗传模型。我们还获得了携带 EGFr 超形态等位基因 dsk5 的小鼠，该基因对配体激活的反应更强烈。我们期望确定参与肝癌发生的特定 ErbB 受体和下游途径。这些研究应有助于开发预防或治疗人类肝癌干预措施的分子靶点。公共卫生相关性：肝细胞癌 (HCC) 或肝细胞癌是第五大常见癌症，也是癌症死亡的第三大原因；过去 25 年来，美国 HCC 的发病率上升了 70% 以上。有重要证据表明，ErbB 酪氨酸激酶蛋白家族在肝癌的发展中发挥着重要作用。它们将是控制 HCC 的极好的目标。使用肝脏 ErbB 蛋白已变得无功能或功能亢进的基因改造小鼠，我们期望确定开发治疗 HCC 的新型化疗的关键靶点。