Transformation of human and murine fibroblasts without viral oncoproteins.
Murine embryo fibroblasts are readily transformed by the introduction of specific combinations of oncogenes; however, the expression of those same oncogenes in human cells fails to convert such cells to tumorigenicity. Using normal human and murine embryonic fibroblasts, we show that the transformation of human cells requires several additional alterations beyond those required to transform comparable murine cells. The introduction of the c-Myc and H-RAS oncogenes in the setting of loss of p53 function efficiently transforms murine embryo fibroblasts but fails to transform human cells constitutively expressing hTERT, the catalytic subunit of telomerase. In contrast, transformation of multiple strains of human fibroblasts requires the constitutive expression of c-Myc, H-RAS, and hTERT, together with loss of function of the p53, RB, and PTEN tumor suppressor genes. These manipulations permit the development of transformed human fibroblasts with genetic alterations similar to those found associated with human cancers and define specific differences in the susceptibility of human and murine fibroblasts to experimental transformation.
Boehm
Jesse S
JS
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St., Dana 710C, Boston, MA 02115-6013, USA.
Hession
Meghan T
MT
Bulmer
Sara E
SE
Hahn
William C
WC
D000818:Animals; D002461:Cell Line, Transformed / Q000201:enzymology / Q000473:pathology* / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000473:pathology* / Q000821:virology; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019098:Telomerase / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; C489427:MYC protein, human; C489428:Myc protein, mouse; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D019098:Telomerase