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 occurs during preneoplastic lung injury in hamsters treated with diethylnitrosamine (DEN) plus hyperoxia. Alterations in oncogene and tumor suppressor gene expression during this process have not been explored.


METHODS
Our goals were: (a) to analyze expression of genes potentially involved in growth and differentiation of PNECs and/or nonneuroendocrine pulmonary epithelial cells (non-PNECs) in hamsters treated for up to 20 weeks with hyperoxia and DEN or the major tobacco-derived nitrosamine, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK); and (b) as a corollary, to determine which cells were most mitotically active by immunostaining for c-myc and proliferating cell nuclear antigen.


RESULTS
Immunohistochemical analyses demonstrated intense PNEC hyperplasia after treatment with either DEN/O2 or NNK/O2. Whereas DEN/O2-induced PNEC hyperplasia spontaneously regressed, NNK/O2-induced PNEC hyperplasia continued to increase up to 20 weeks. Rb transcripts were decreased similarly in lungs from all treatment groups (NNK/O2 = DEN/O2 = DEN alone) in spite of large differences in PNEC hyperplasia between these groups. c-myc was overexpressed in lungs from animals treated with NNK/O2, DEN/O2 and DEN alone, in which c-myc protein 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 hyperplasia is primarily due to PNEC differentiation, suggesting that this model is ideal for studying mechanisms of neuroendocrine differentiation. Paracrine effects of PNEC-derived growth factors may then contribute to dysregulation of non-PNEC growth preceding the ultimate development of non-neuroendocrine lung tumors in nitrosamine-treated hamsters.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
M E
ME
Sunday
C G
CG
Willett
K
K
Patidar
S A
SA
Graham
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D002454:Cell Differentiation; D002455:Cell Division; D006224:Cricetinae; D017931:DNA Primers; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D016161:Genes, Retinoblastoma; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D016259:Genes, myc; D016158:Genes, p53; D011905:Genes, ras; D006965:Hyperplasia; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009602:Nitrosamines / Q000633:toxicity; D015345:Oligonucleotide Probes; D009857:Oncogenes / Q000187:drug effects; D016133:Polymerase Chain Reaction / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf; D011519:Proto-Oncogenes / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D002273:Carcinogens; D017931:DNA Primers; D009602:Nitrosamines; D015345:Oligonucleotide Probes; D011518:Proto-Oncogene Proteins; D004052:Diethylnitrosamine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf