Inductible mouse models for oral cancer

口腔癌诱导小鼠模型

基本信息

批准号：
7157638
负责人：
CARLOS CAULIN
金额：
$ 5.24万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-13 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7157638
关键词：
Address Adult Alleles Antineoplastic Agents Area Breast Cancer Etiology Cancer Patient Cervical Cessation of life Colorectal Cancer Development Diagnosis Diagnostic Neoplasm Staging EGFR Protein Overexpression Early Diagnosis Epidermal Growth Factor Receptor Epigenetic Process Epithelial Exhibits Frequencies Gene Mutation Genes Genetic Glioblastoma Human Incidence Knock-out Lip structure Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Modeling Molecular Mouth Neoplasms Mus Mutation Numbers Oncogene Activation Oral cavity Oral mucous membrane structure Pathway interactions Play Pre-Clinical Model Prevention intervention Process Property Protein Overexpression Purpose Receptor Signaling Relative (related person)Reporting Retinoblastoma Role Signal Pathway Somatic Mutation Squamous cell carcinoma Staging Survival Rate System TP53 gene Testing Therapeutic Agents Tissues Tongue Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins Tumor stage Tumor-Suppressor Gene Inactivation United States base c-erbB-1 Proto-Oncogenes gain of function gain of function mutation human cancer mouse model in vivo Model keratin 14, K14 malignant mouth neoplasm mouse model novel therapeutics oral cavity epithelium tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): Oral cancer is the seventh most common form of cancer and causes 8,000 deaths in the United States each year and 128,000 worldwide. Similar to other tumor types, it is widely accepted that the formation of oral cancer is a multi-step process that results from the accumulation of genetic alterations. The high frequency of genetic and epigenetic alterations found in certain genes strongly suggests a causal role in the development of oral cancer. Our long-term objective is to generate transgenic mice carrying inducible genetic alterations that closely mimic some of the most common mutations found in human cancer of the oral cavity. Although a large number of genetic alterations have been reported in oral cancer patients, three different molecular pathways seem to be the major targets of mutations, namely the p53, retinoblastoma (Rb) and Epidermal Growth Factor Receptor (EGFR) signaling pathways. Accordingly, the gene alterations most frequently found in oral cancer include EGFR overexpression, p53 mutations (such as the gain-of-function p53R175H) and inactivation of the INK4a/ARF locus, which functions at least in part as a negative regulator of the Rb pathway. We hypothesize that these mutations that have a high incidence in oral cancer patients play a causal role in the development of cancer of the oral cavity. To test this hypothesis we will use an inducible system to generate mouse models that exhibit p53 mutations, EGFR overexpression or inactivation of the INK4a/ARF locus only in the oral cavity. These models have several advantages over conventional transgenic/knockout models: the mutation can be targeted to a restricted area of the tissue and the moment of tumor initiation can be chosen. Therefore, they will closely mimic the sporadic focal accumulation of somatic mutations found in human tumors. These mouse models will be useful not only to better understand the molecular mechanisms of oral cancer development, but also as preclinical models for testing therapeutic agents for prevention and intervention of oral cancer.

描述（由申请人提供）：口腔癌是第七大最常见的癌症，每年在美国导致 8,000 人死亡，在全球导致 128,000 人死亡。与其他肿瘤类型类似，人们普遍认为口腔癌的形成是一个多步骤的过程，是基因改变积累的结果。某些基因中发现的高频率遗传和表观遗传改变强烈表明其在口腔癌的发生中具有因果作用。我们的长期目标是培育携带可诱导基因改变的转基因小鼠，这些基因改变与人类口腔癌中发现的一些最常见突变非常相似。尽管口腔癌患者存在大量基因改变，但三种不同的分子通路似乎是突变的主要目标，即p53、视网膜母细胞瘤(Rb)和表皮生长因子受体(EGFR)信号通路。因此，口腔癌中最常见的基因改变包括 EGFR 过度表达、p53 突变（例如功能获得性 p53R175H）和 INK4a/ARF 位点失活，该位点至少部分充当 Rb 的负调节因子途径。我们假设这些在口腔癌患者中发生率较高的突变在口腔癌的发展中起着因果作用。为了检验这一假设，我们将使用诱导系统来生成仅在口腔中表现出 p53 突变、EGFR 过表达或 INK4a/ARF 位点失活的小鼠模型。与传统的转基因/敲除模型相比，这些模型有几个优点：突变可以针对组织的有限区域，并且可以选择肿瘤发生的时刻。因此，它们将密切模仿人类肿瘤中发现的体细胞突变的零星局部积累。这些小鼠模型不仅有助于更好地了解口腔癌发展的分子机制，而且还可作为测试预防和干预口腔癌的治疗药物的临床前模型。