Inductible mouse models for oral cancer

口腔癌诱导小鼠模型

基本信息

批准号：
7496741
负责人：
CARLOS CAULIN
金额：
$ 30.03万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496741
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

Oral cancer is the seventh most common form o_ 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 thq development of oral cancer. Our long-term objective is to generate transgenic mice carrying inducibh genetic alterations that closely mimic some of the most common mutations found in human cancer of the or_ 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.

口腔癌是O_癌症的第七种最常见的形式，每个人在美国造成8,000例死亡全球和128,000年。与其他肿瘤类型相似，被广泛认为是口服的形成癌症是由遗传改变的积累导致的多步骤过程。高频在某些基因中发现的遗传和表观遗传学改变强烈表明在THQ中起因作用口腔癌的发展。我们的长期目标是产生携带诱导型的转基因小鼠遗传变量紧密模仿了OR_人类癌症中一些最常见的突变腔。尽管口腔癌患者已经报道了大量的遗传改变，但三个不同的分子途径似乎是突变的主要靶标，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，基因改变口腔癌中最常发现的包括EGFR过表达，p53突变（例如 - 功能p53r175h）和ink4a/arf基因座的灭活，至少部分作用为负 RB路径的调节器。我们假设这些在口腔癌中发病率高的突变患者在口腔癌的发展中起因果作用。为了检验这个假设，我们将使用一个可诱导的系统，用于生成显示p53突变，EGFR过表达或仅在口腔中的Ink4a/arf基因座的灭活。这些模型有几个优势常规的转基因/敲除模型：突变可以针对组织的限制区域可以选择肿瘤开始的力矩。因此，它们将密切模仿零星的焦点在人类肿瘤中发现的体细胞突变的积累。这些鼠标模型不仅有用更好地了解口腔癌发展的分子机制，但也可以作为临床前模型测试预防和干预口腔癌的治疗剂。