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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：
7876518
负责人：
WILLIAM E RUSSELL
金额：
$ 19.72万
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/7876518
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 ERBB2 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 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 Research 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(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的最严重后果之一就是肝细胞癌的发展。肝癌是全球第五大常见癌症和第三大癌症死亡原因，每年导致100多万人死亡。它的发病率正在上升，特别是在美国，在过去的25年里，它增加了70%。没有有效的二级预防或系统治疗。长期以来，我们一直对表皮生长因子(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。Gefitinib是一种EGFR酪氨酸激酶的小分子抑制剂，它将减少N-亚硝酸二乙胺(DEN)暴露的大鼠肝细胞癌的发生，从而导致肝损伤、肝硬变，最终导致肝细胞癌。吉非替尼和其他EGFR酪氨酸激酶抑制剂最近在治疗人类肝癌方面显示出希望，这表明ErbB蛋白在肝细胞癌发生中的重要作用以及与人类肝癌动物模型的相关性。我们已经证明，在正常情况下，只有三种ErbB蛋白在肝脏中表达(EGFR、ErbB2和ErbB3)，并且它们在肝细胞中的表达存在发育调节模式。尽管ErbB蛋白经常被孤立地研究，但它们是高度相互作用的，并形成信号同源和异源二聚体。在人类肝细胞癌中，ErbB3是持续上调的217个蛋白质之一(共检测到9000个)；EGFR或ErbB2(但不是两者)往往与ErbB3一起上调。研究中的假设是ErbB酪氨酸激酶在啮齿类动物模型中对肝细胞癌的发生至关重要。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，以评估它们在肝细胞癌的发生和发展中的重要性。我们已经产生了肝细胞特异性的单基因和双基因ErbB基因敲除小鼠。这些动物发育正常，是分析ErbB缺失背景下从肝炎到肝硬变再到肝细胞癌(肝细胞癌)进展的理想遗传模型。我们还获得了一只携带EGFR等位基因dsk5的小鼠，该等位基因对配体激活的反应更强烈。我们希望确定与肝癌发生有关的特异性ErbB受体及其下游通路。这些研究应该有助于开发干预措施的分子靶点，以预防或治疗人类肝细胞癌。公共卫生相关性：肝细胞癌(简称肝细胞癌)是第五大常见癌症，也是导致癌症死亡的第三大原因；在过去的25年里，美国的肝癌发病率上升了70%以上。有重要证据表明，一种名为ErbB酪氨酸激酶的蛋白家族在肝癌的发展中发挥了作用；它们将是控制肝细胞癌的极好靶点。利用基因改变的小鼠，其中肝脏ErbB蛋白已经变得没有功能或功能亢进，我们希望为开发治疗肝癌的新化疗药物确定关键靶点。