A mouse model of human oral-esophageal cancer

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Abstract
Squamous cancers of the oral cavity and esophagus are common worldwide, but no good genetically based animal model exists. A number of environmental factors as well as genetic alterations have been identified in these cancers, yet the specific combination of genetic events required for cancer progression remains unknown. The Epstein-Barr virus ED-L2 promoter (L2) can be used to target genes in a specific fashion to the oral-esophageal squamous epithelium. To that end, we generated L2–cyclin D1 (L2D1+) mice and crossbred these with p53-deficient mice. Whereas L2D1+ mice exhibit a histologic phenotype of oral-esophageal dysplasia, the combination of cyclin D1 expression and p53 deficiency results in invasive oral-esophageal cancer. The development of the precancerous lesions was significantly reversed by the application of sulindac in the drinking water of the L2D1+/p53+/– mice. Furthermore, cell lines derived from oral epithelia of L2D1+/p53+/– and L2D1+/p53–/– mice, but not control mice, formed tumors in athymic nude mice. These data demonstrate that L2D1+/p53+/– mice provide a well-defined, novel, and faithful model of oral-esophageal cancer, which allows for the testing of novel chemopreventive, diagnostic, and therapeutic approaches.