v-sis oncogene-induced transformation of human fibroblasts into cells capable of forming benign tumors.
Normal human fibroblasts do not synthesize platelet-derived growth factor (PDGF), but they respond to its mitogenic action. In contrast, cells from several human fibrosarcomas have been shown to synthesize PDGF at significant levels. To investigate the possible role of PDGF expression in the development of tumors of mesenchymal origin in humans, we transfected a plasmid carrying the v-sis oncogene and a selectable marker into an infinite lifespan, non-tumorigenic human fibroblast cell strain, MSU-1.1. The v-sis gene codes for a protein homolog of PDGF-B. Of the six independent drug-resistant transfectants clonally isolated, three expressed a relatively low level of v-sis mRNA and protein, grew to a saturation density only 2-2.5 times higher than MSU-1.1 cells, did not form colonies in agar, were not growth factor independent and did not form tumors. The other three expressed v-sis mRNA and protein at a high level, grew to a very high saturation density (> 750,000 cells/cm2), replicated in medium lacking exogenous growth factors almost as rapidly as with 10% serum, formed large colonies in 0.33% agarose and, when injected into athymic mice, formed tumors that grew rapidly. Tumors that were removed after 6 weeks were classified as benign (fibromas). However, several of the tumors that were left in the animals for 6 months developed focal areas of cells showing features of poorly differentiated spindle cell or round cell sarcomas. Similarly, cells isolated from a very large sized agarose colony formed by one of the other v-sis strains expressed very high levels of v-sis mRNA and protein and formed large, very fast growing benign tumors. Re-injection of cells from the tumors yielded tumors composed of two distinct areas: spindle cell fibromas and high grade sarcomas. These results suggest that if mesenchymal cells in the body were induced to express their PDGF-B gene, this could lead to the formation of benign tumors of mesenchymal origin. The system described can serve as a model for studying the mechanisms of formation of such tumors in humans and their progression to the malignant state.
Yang
D
D
Department of Microbiology, Michigan State University, East Lansing 48824-1316.
Kohler
S K
SK
Maher
V M
VM
McCormick
J J
JJ
D000818:Animals; D001483:Base Sequence; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D004351:Drug Resistance; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005350:Fibroma / Q000473:pathology; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007621:Karyotyping; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012685:Sepharose; D013498:Suramin / Q000494:pharmacology; D014162:Transfection
D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D013498:Suramin; D012685:Sepharose; D017479:Receptors, Platelet-Derived Growth Factor