A transgenic mouse model of metastatic carcinoma involving transdifferentiation of a gastric epithelial lineage progenitor to a neuroendocrine phenotype

Human neuroendocrine cancers (NECs) arise in various endoderm-derived epithelia, have diverse morphologic features, exhibit a wide range of growth phenotypes, and generally have obscure cellular origins and ill-defined molecular mediators of initiation and progression. We describe a transgenic mouse model of metastatic gastric cancer initiated by expressing simian virus 40 large tumor antigen (SV40 TAg), under control of regulatory elements from the mouse Atp4b gene, in the progenitors of acid-producing parietal cells. Parietal cells normally do not express endocrine or neural features, and Atp4b-Cre bitransgenic mice with a Cre reporter confirmed that the Atp4b regulatory elements are not active in gastric enteroendocrine cells. GeneChip analyses were performed on laser capture microdissected SV40 TAg-expressing cells in preinvasive foci and invasive tumors. Genes that distinguish invasive from preinvasive cells were then hierarchically clustered with DNA microarray datasets obtained from human lung and gastric cancers. The results, combined with immunohistochemical and electron microscopy studies of Apt4b-SV40 TAg stomachs, revealed that progression to invasion was associated with transdifferentiation of parietal cell progenitors to a neuroendocrine phenotype, and that invasive cells shared molecular features with NECs arising in the human pulmonary epithelium, including transcription factors that normally regulate differentiation of various endocrine lineages and maintain neural progenitors in an undifferentiated state. The 399 mouse genes identified as regulated during acquisition of an invasive phenotype and concomitant neuroendocrine transdifferentiation, plus their human orthologs associated with lung NECs, provide a foundation for molecular classification of NECs arising in other tissues and for genetic tests of the molecular mechanisms underlying NEC pathogenesis.