Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines.
We studied tumor necrosis factor (TNF)-alpha as a candidate cytokine to promote neuroendocrine cell differentiation in a nitrosamine-hyperoxia hamster lung injury model. Differential screening identified expression of the genes modulated by TNF-alpha preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H526 were treated with TNF-alpha for up to 2 wk. Both cell lines demonstrated rapid induction of gastrin-releasing peptide (GRP) mRNA; H82 cells also expressed aromatic-L-amino acid decarboxylase mRNA within 5 min after TNF-alpha was added. Nuclear translocation of nuclear factor-kappaB immunostaining occurred with TNF-alpha treatment, suggesting nuclear factor-kappaB involvement in the induction of GRP and/or aromatic-L-amino acid decarboxylase gene expression. We also demonstrated dense core neurosecretory granules and immunostaining for proGRP and neural cell adhesion molecule in H82 cells after 7-14 days of TNF-alpha treatment. We conclude that TNF-alpha can induce phenotypic features of neuroendocrine cell differentiation in SCLC cell lines. Similar effects of TNF-alpha in vivo may contribute to the neuroendocrine cell differentiation/hyperplasia associated with many chronic inflammatory pulmonary diseases.
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
K J
KJ
Haley
K
K
Patidar
F
F
Zhang
R L
RL
Emanuel
M E
ME
Sunday
D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000096:biosynthesis / Q000235:genetics; D015415:Biomarkers; D018288:Carcinoma, Small Cell / Q000473:pathology*; D002454:Cell Differentiation; D006224:Cricetinae; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure; D019886:Gastrin-Releasing Peptide / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D018496:Hyperoxia; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D009490:Neurosecretory Systems / Q000166:cytology* / Q000187:drug effects; D009602:Nitrosamines; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015415:Biomarkers; D016328:NF-kappa B; D009602:Nitrosamines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019886:Gastrin-Releasing Peptide; D001142:Aromatic-L-Amino-Acid Decarboxylases