Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms

We initiated a transgenic model for primary pulmonary neuroendocrine cell ( PNEC) hyperplasia/neoplasia using v-Ha-ras driven by the neural/neuroendocr ine (NE)-specific calcitonin promoter (rascal). Previously, we showed that nitrosamine treated rodents develop PNEC hyperplasia but non-NE lung tumors , with variable outcomes presumably reflecting ras activation in multiple c ell lineages. Interestingly, all rascal transgenic mouse lineages develop h yperplasias of NE and non-NE cells but mostly non-NE lung carcinomas, with rascal mRNA in differentiated PNECs and tumor cells. Analyses of embryonic lung demonstrate rascal mRNA in undifferentiated epithelium, consistent wit h expression in a common pluripotent precursor cell. These unexpected obser vations indicate that v-Ha-ras can lead to both NE and non-NE hyperplasia/n eoplasia in vivo, opening new avenues for studies of lung carcinogenesis.