In vivo tumorigenicity and in vitro sensitivity to tumor-necrosis-factor alpha mediated killing of c-Ha-ras-transformed cells.
Cellular subclones of high and low tumorigenicity obtained from a mouse c-Ha-ras-transformed clone, were examined for their sensitivity to tumor-necrosis-factor (TNF)-mediated cytotoxicity. Cells of the highly tumorigenic subclones showed a significantly enhanced resistance to the cytotoxic effect of TNF plus cyclohexamide (CHI) as compared to cells of the low-tumorigenic subclones. The enhanced resistance to TNF+CHI was not due to a lower expression of TNF receptors on the cells. The c-Ha-ras-transfected cells were transformed and maintained in culture only (C cells). In vivo passage of cells of the initially low-tumorigenic c-Ha-ras subclones through the mouse significantly enhanced the tumorigenic potential of these CTC cells (culture/tumor/culture). In correlation with their enhanced tumorigenicity, the CTC cells were highly resistant to TNF-mediated cytotoxicity as compared to C cells of the same subclone. Furthermore, the involvement of TNF in determining the tumorigenic phenotype of the c-Ha-ras-transformed cells was demonstrated in a more direct manner. Cells of a c-Ha-ras-transformed low-tumorigenic, highly TNF-sensitive subclone were selected by repeated cycles of in vitro exposure to TNF alpha. As a result, a stable, highly TNF-resistant population of cells emerged. These TNF-resistant cells caused more tumors in mice as compared to their original TNF-sensitive cells. These results show that the resistance to the cytotoxic effect of TNF plus cyclohexamide may be involved, at least partially, in the tumorigenic potential of c-Ha-ras-transformed cells and suggest a possible role for TNF in the enhancement of the tumorigenic potential of these cells in mice.
Gonen
B
B
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Kahana
O
O
Witz
I P
IP
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D002461:Cell Line, Transformed / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology*; D003513:Cycloheximide / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression; D011905:Genes, ras; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide