Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor.
At least 70% of small cell lung cancer (SCLC) tumors and tumor-derived cell lines coexpress the genes for stem cell factor (SCF) and its receptor, the c-kit proto-oncogene. To assess the impact of coexpression of the growth factor and receptor on SCLC growth, the NCI-H146 SCLC cell line, which expresses only SCF, was transfected with a c-kit expression vector. Kit protein immunoprecipitated from the transfected cells had a constitutive level of tyrosine phosphorylation, and these cells grew more vigorously in serum-free medium compared to control-transfected cells. This growth advantage could be blocked by the addition of the tyrosine kinase inhibitor herbimycin A. Growth of the c-kit-transfected cells could be further enhanced by the addition of bombesin or insulin-like growth factor-1, suggesting that the SCF/c-kit autocrine loop could function cooperatively with other SCLC autocrine loops. To further investigate the importance of this autocrine loop, a cell line that naturally coexpresses SCF and c-kit was transfected with a kinase-defective c-kit gene. Cells transfected with the defective gene showed a marked decrease in their ability to grow under growth factor-free conditions compared to cells transfected with the empty expression vector. Taken together, these studies demonstrate that the coexpression of the stem cell factor and c-kit genes is a major contributor to the growth factor independence of SCLC.
Department of Medicine, Medical College of Virginia, Richmond, USA.
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Krystal
S J
SJ
Hines
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D001839:Bombesin / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D015870:Gene Expression; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019089:Stem Cell Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D006133:Growth Substances; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019089:Stem Cell Factor; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D001839:Bombesin