Malignant transformation of human fibroblasts by a transfected N-ras oncogene.
The only ras oncogene as yet identified in cells from human fibrosarcomas is N-ras, but the relationship between N-ras oncogene expression and the malignant state of these cell lines is not known. To determine if expression of an N-ras oncogene causes human cells to become malignant, we transfected the N-ras oncogene from human leukemia cell line 8402, cloned into a high expression vector pSV N-ras, into MSU-1.1 cells, a nontumorigenic, infinite life span fibroblast cell strain with a normal morphology and a stable near-diploid karyotype. The transformants formed distinct foci composed of morphologically transformed cells. Cells from such foci expressed higher than normal levels of N-ras protein, exhibited growth factor independence, and formed large colonies in soft agar at a high frequency. Injection of progeny of these focus-derived cells s.c. into athymic mice resulted in progressively growing, invasive malignant tumors (round cell, spindle cell, or giant cell sarcomas) which reached a diameter of 6 mm in 3 to 4 weeks. Injection of focus-derived or tumor-derived cells i.v. resulted in tumors in various organs of the mice. The focus-derived cell strain tested, as well as the majority of the cells derived from the tumor it produced, exhibited the same near-diploid karyotype as the parental MSU-1.1 cells. Cells transfected with an N-ras oncogene that was expressed at a normal level formed only a single, indistinct focus, and cells from that focus were not malignant.
Carcinogenesis Laboratory, Michigan State University, East Lansing 48824-1316.
D M
DM
Wilson
D J
DJ
Yang
J E
JE
Dillberger
S E
SE
Dietrich
V M
VM
Maher
J J
JJ
McCormick
D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002871:Chromosome Banding; D003470:Culture Media; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D011905:Genes, ras; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009693:Nucleic Acid Hybridization; D010957:Plasmids; D015183:Restriction Mapping; D014162:Transfection
D003470:Culture Media; D004273:DNA, Neoplasm; D006133:Growth Substances