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的生长，分化和再生的机制。肝细胞癌（HCC）的发展是无序的肝细胞生长和分化的最深刻后果之一。 HCC是全球癌症死亡的第五大癌症，也是第三大主要原因，每年导致超过100万人死亡。它的发病率正在上升，尤其是在美国，在过去的25年中，它的发病率上升了70％。没有有效的二级预防或全身治疗。我们对表皮生长因子（EGF及其同源物）的作用以及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长期存在。吉非替尼是EGFR酪氨酸激酶的小分子抑制剂，将减少暴露于N-亚硝基二乙基胺（DEN）的大鼠中HCC的发育，从而诱导肝脏损伤，肝硬化和最终HCC。吉非替尼和其他EGFR酪氨酸激酶抑制剂最近在治疗人HCC方面表现出了希望，表明ERBB蛋白在肝细胞癌中的重要作用以及动物模型对人HCC的相关性。我们已经表明，在正常情况下，只有三种ERBB蛋白在肝脏中表达（EGFR，ERBB2和ERBB3），并且肝细胞的表达中有一种发育调节的模式。尽管经常分离研究它们，但ERBB蛋白具有高度互动性，并形成信号传导同二聚体和异二聚体。在Human HCC中，ERBB3是一贯上调的217种蛋白质之一（在9000次检查中）之一。 EGFR或ERBB2（但并非两者）都与ERBB3一起上调。所研究的假设是，ERBB酪氨酸激酶对于DEN啮齿动物模型中HCC的发展至关重要。我们提出了一项系统的研究，对肝细胞中这些分子的遗传缺失的后果，以评估它们在HCC的启动和进展中的重要性。我们已经产生了肝细胞特异性单基因和双基因ERBB敲除小鼠。这些动物正常发展，是分析ERBB损失环境中从肝炎到肝硬化再到肝细胞癌（HCC）的理想遗传模型。我们还可以访问EGFR DSK5的型鼠标，该小鼠对配体激活的响应更加牢固地信号。我们期望鉴定肝癌发生涉及的特定ERBB受体和下游途径。这些研究应有助于开发用于预防或治疗人类HCC的干预措施的分子靶标。公共卫生相关性：肝细胞癌（HCC）或肝细胞癌是第五大癌症，是癌症死亡的第三主要原因。在过去的25年中，HCC的发病率上升了70％以上。有大量证据表明，称为ERBB酪氨酸激酶的蛋白质家族在肝癌的发展中起作用。它们将是控制HCC的非常好的目标。利用肝ERBB蛋白的遗传改变的小鼠进行了非功能或过度功能，我们希望确定开发新型化学疗法以治疗HCC的关键靶标。