The role of EGFR signaling in progression of Kras-induced pacreatic tumors

EGFR 信号传导在 Kras 诱导的胰腺肿瘤进展中的作用

• 批准号: 7135994
• 负责人: ANNA L MEANS
• 金额: $ 11.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7135994
• 关键词: adenocarcinoma; adenoma; biomarker; emotions; epigenetics; epithelium; gene mutation; genes; genetics; growth factor; keratin; lead; ligands; model; neoplasm /cancer; pancreas; pancreas neoplasms; role; stainings

DESCRIPTION (provided by applicant): Project Summary: The process of tumorigenesis generally results from multiple, sequential genetic and epigenetic changes that affect a number of cellular processes including growth, survival, invasiveness, and metastatic capabilities of the tumor. Pancreatic ductal adenocarcinoma, the primary cancer of the pancreas, is associated with activating mutations in the Kras gene, loss of multiple tumor suppressor genes, and increased expression of epidermal growth factor receptor (EGFR) signaling components. Understanding how each of these events affects tumorigenesis is essential to developing treatment that will target the most critical components of tumor growth, survival, and metastasis. Furthermore, understanding which genetic or epigenetic events occur early in tumorigenesis may lead to biomarkers for earlier detection of pancreatic cancer. Mouse models have recently delineated Kras mutation as a potent initiator of pancreatic tumorigenesis. In addition to Kras mutation, the majority of all pancreatic adenocarcinomas express abnormally high levels of the growth factors that bind to EGFR as well as high levels of EGFR itself. Due to this prevalence in human tumors and in early precursor lesions, we hypothesize that EGFR signaling contributes to early stages in pancreatic neoplasia. We will test this hypothesis in two ways, by increasing or by decreasing EGFR signaling in conjunction with activation of the Kras oncogene, using mouse models of pancreatic ductal adenocarcinoma. We will increase EGFR signaling via transgenic overexpression of the growth factor HB-EGF, and we will decrease EGFR signaling by using mice with a mutation in the Egfr gene. These experiments will indicate what stage of tumorigenesis is affected by EGFR signaling as well as determining if and when EGFR is an appropriate chemotherapeutic target in pancreatic cancer patients. This work will also lead to further studies on the mechanisms of EGFR action and regulation in pancreatic tumorigenesis. Relevance: Pancreatic cancer is the 5th leading cause of cancer deaths in this country. This is due both to difficulty in detecting early stage cancers and to this cancer being refractory to traditional therapies. The studies proposed here investigate EGFR signaling as a potential biomarker and/or therapeutic target, by studying its effects on tumorigenesis in a mouse model of pancreatic cancer.

描述（由申请人提供）： 项目摘要：肿瘤发生过程通常是由多个连续的遗传和表观遗传变化引起的，这些变化影响许多细胞过程，包括肿瘤的生长、存活、侵袭和转移能力。胰腺导管腺癌是胰腺的原发性癌症，与 Kras 基因的激活突变、多个肿瘤抑制基因的丢失以及表皮生长因子受体 (EGFR) 信号成分表达增加有关。了解这些事件如何影响肿瘤发生对于开发针对肿瘤生长、存活和转移最关键组成部分的治疗方法至关重要。此外，了解肿瘤发生早期发生的遗传或表观遗传事件可能会产生用于早期检测胰腺癌的生物标志物。小鼠模型最近将 Kras 突变描述为胰腺肿瘤发生的有效引发剂。除了 Kras 突变之外，大多数胰腺腺癌都表达异常高水平的与 EGFR 结合的生长因子以及高水平的 EGFR 本身。由于这种在人类肿瘤和早期前驱病变中的普遍存在，我们假设 EGFR 信号传导有助于胰腺肿瘤的早期阶段。我们将使用胰腺导管腺癌小鼠模型，以两种方式检验这一假设，即增加或减少 EGFR 信号传导以及 Kras 癌基因的激活。我们将通过生长因子 HB-EGF 的转基因过度表达来增加 EGFR 信号传导，并通过使用 Egfr 基因突变的小鼠来减少 EGFR 信号传导。这些实验将表明肿瘤发生的哪个阶段受到 EGFR 信号传导的影响，并确定 EGFR 是否以及何时成为胰腺癌患者合适的化疗靶点。这项工作也将导致对 EGFR 在胰腺肿瘤发生中的作用和调节机制的进一步研究。相关性：胰腺癌是该国第五大癌症死亡原因。这是因为早期癌症难以检测，而且这种癌症对传统疗法难以治愈。本文提出的研究通过研究 EGFR 信号传导对胰腺癌小鼠模型中肿瘤发生的影响，将其作为潜在的生物标志物和/或治疗靶点。