Inductible mouse models for oral cancer

口腔癌是第七种最常见的癌症，每年在美国造成8000人死亡，在全球造成128000人死亡。与其他类型的肿瘤类似，人们普遍认为口腔癌的形成是一个多步骤的过程，是遗传改变积累的结果。在某些基因中发现的高频率的遗传和表观遗传改变强烈表明在口腔癌的发展中起因果作用。我们的长期目标是产生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的突变非常相似。尽管在口腔癌患者中已经报道了大量的遗传改变，但三种不同的分子通路似乎是突变的主要靶点，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过表达、p53突变（如功能获得的p53R175H）和INK4a/ARF位点失活，INK4a/ARF位点至少在一定程度上是Rb通路的负调控因子。我们假设这些在口腔癌患者中高发病率的突变在口腔癌的发展中起着因果作用。为了验证这一假设，我们将使用一个诱导系统来产生仅在口腔中表现出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/基因敲除模型相比，这些模型有几个优点：突变可以靶向组织的有限区域，并且可以选择肿瘤启动的时刻。因此，它们将密切模仿在人类肿瘤中发现的散发性局灶性体细胞突变积累。这些小鼠模型不仅有助于更好地了解口腔癌发生的分子机制，而且还可作为临床前模型，用于测试预防和干预口腔癌的治疗药物。

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.