c-Myc suppresses the tumorigenicity of lung cancer cells and down-regulates vascular endothelial growth factor expression.
The c-myc oncogene is frequently amplified in cells grown from lung tumors and has been linked to the malignancy of these cancers. In support of this, c-myc transfection enhances the in vitro proliferation and soft agar cloning of human small cell lung cancer (SCLC) cells. In this study, we surprisingly found that c-myc expression suppressed the formation of tumors by SCLC cells in athymic nude mice. c-myc expression down-regulated the protein and transcript for vascular endothelial growth factor (VEGF) in these SCLC cells, as well as VEGF transcript in rat fibroblasts manipulated for c-myc expression and in liver cells of c-myc-transgenic mice. Finally, bivariate and multivariate analyses demonstrated that the probability of tumor formation from lung cancer cell lines was negatively correlated with the relative expression of c-Myc, positively correlated with the relative expression of VEGF, and that the latent time to tumor formation was increased by the expression of c-Myc and decreased by the expression of VEGF. We hypothesize that, for lung cancer cells, c-Myc suppresses the formation of tumors in vivo by down-regulating VEGF, and that the amplification of c-myc seen in cells grown from lung tumors with a poor prognosis is an artifact of selection for growth in vitro.
Barr
L F
LF
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21204, USA.
Campbell
S E
SE
Diette
G B
GB
Gabrielson
E W
EW
Kim
S
S
Shim
H
H
Dang
C V
CV
D000704:Analysis of Variance; D000818:Animals; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005784:Gene Amplification; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors