MODULATION OF ONCOGENE AND TUMOR-SUPPRESSOR GENE-EXPRESSION IN A HAMSTER MODEL OF CHRONIC LUNG INJURY WITH VARYING DEGREES OF PULMONARY NEUROENDOCRINE CELL HYPERPLASIA

BACKGROUND: Intense pulmonary neuroendocrine cell (PNEC) hyperplasia o ccurs during preneoplastic lung injury in hamsters treated with diethy lnitrosamine (DEN) plus hyperoxia. Alterations in oncogene and tumor s uppressor gene expression during this process have not been explored. EXPERIMENTAL DESIGN: Our goals were: (a) to analyze expression of gene s potentially involved in growth and differentiation of PNECs and/or n onneuroendocrine pulmonary epithelial cells (non-PNECs) in hamsters tr eated for up to 20 weeks with hyperoxia and DEN or the major tobacco-d erived nitrosamine, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NN K); and (b) as a corollary, to determine which cells were most mitotic ally active by immunostaining for c-myc and proliferating cell nuclear antigen. RESULTS: Immunohistochemical analyses demonstrated intense P NEC hyperplasia after treatment with either DEN/O-2 or NNK/O-2. Wherea s DEN/O-2-induced PNEC hyperplasia spontaneously regressed, NNK/O-2-in duced PNEC hyperplasia continued to increase up to 20 weeks. Rb transc ripts were decreased similarly in lungs from all treatment groups (NNK /O-2 = DEN/O-2 = DEN alone) in spite of large differences in PNEC hype rplasia between these groups. c-myc was overexpressed in lungs from an imals treated with NNK/O-2, DEN/O-2 and DEN alone, in which c-myc prot ein immunostaining occurred predominantly in non-PNECs. Proliferating cell nuclear antigen immunostaining confirmed that non-PNECs were most mitotically active. CONCLUSIONS: These data indicate that PNEC hyperp lasia is primarily due to PNEC differentiation, suggesting that this m odel is ideal for studying mechanisms of neuroendocrine differentiatio n. Paracrine effects of PNEC-derived growth factors may then contribut e to dysregulation of non-PNEC growth preceding the ultimate developme nt of non-neuroendocrine lung tumors in nitrosamine-treated hamsters.