Our long-term goal is to elucidate the molecular mechanisms of esophageal adenocarcinoma (EAC), and to design mechanism-based chemoprevention strategies. Esophago-gastroduodenal anastomosis (EGDA) with rats mimics the development of human EAC by introducing mixed reflux of gastric and duodenal contents into the esophagus. Nevertheless, this rat model has its limitations because few genetically modified rat strains are available for mechanistic and chemopreventive studies of EAC. In this proposal, we plan to establish a mouse model of EAC by combining tissue-specific genetic modification and surgically induced gastroesophageal reflux, with the following specific aims: 1. To generate mice with p53 gene deletion in esophageal squamous epithelial cells (keratin 14-expressing cells) or columnar epithelial cells (villin-expressing cells) by crossing K14-cre or Vil-cre mice with p53loxP/loxP mice. Efficiency of p53 gene deletion will be confirmed by examining Cre expression with immunohistochemistry and p53 gene deletion with microdissection PCR in mouse tissues. K14-cre; p53loxP/loxP mice lose p53 gene in normal esophageal squamous epithelial cells, while Vil-cre; p53loxP/loxP mice start to lose p53 gene in columnar epithelial cells at the metaplasia/precancerous stage. These mice mimic human patients with germ-line and acquired p53 mutations, respectively. 2. To induce EAC in K14-cre;p53loxP/loxP mice and Vil-cre;p53loxP/loxP mice with EGDA surgery, and characterize histopathological progression and molecular alterations in mouse esophagus. These data will be compared with human samples to establish the relevance and similarity of the mouse model to human disease. The proposed mouse model is expected to induce EAC with tissue-specific genetic defects and surgery-induced gastroesophageal reflux. This unique model system will lay down a solid foundation for future mechanism-based chemopreventive studies on EAC. ? ? ?
| Hao, Jing; Liu, Ba; Yang, Chung S et al. (2009) Gastroesophageal reflux leads to esophageal cancer in a surgical model with mice. BMC Gastroenterol 9:59 |
