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Effect of cellular determination on oncogenic transformation by chemicals and oncogenes
M A Harrington1, F Gonzales, P A Jones
1USC Comprehensive Cancer Center, University of Southern California, Los Angeles 90033.
Abstract:
Three developmentally determined myogenic cell lines derived from C3H 10T1/2 C18 (10T1/2) mouse embryo cells treated with 5-azacytidine were compared with the parental 10T1/2 line for their susceptibility to oncogenic transformation by 3-methylcholanthrene or the activated human c-Ha-ras oncogene. Neither the 10T1/2 cells nor the myogenic derivatives grew in soft agar or formed tumors in nude mice. In contrast to 10T1/2 cells, the three myogenic derivatives were not susceptible to transformation by 3-methylcholanthrene, so that cellular determination altered the response of 10T1/2 cells to chemical carcinogen. On the other hand, all cell types were transformed to a tumorigenic phenotype following transfection with the activated c-Ha-ras gene. The transfected myogenic cells expressed both the c-Ha-ras gene and the muscle determination gene MyoD1. In contrast to other reports, the presence of as many as six copies of the c-Ha-ras gene per genome did not prevent the formation of striated muscle cells which expressed immunologically detectable muscle-specific myosin. The expression of the c-Ha-ras gene does not therefore necessarily preclude the expression of the determination gene for myogenesis or prevent end-stage myogenic differentiation.
Insights
Cellular determination in myogenic cell lines altered their response to chemical carcinogens. However, oncogene activation via c-Ha-ras still induced tumorigenesis, without preventing muscle cell differentiation.
Area of Science:
- Cell Biology
- Developmental Biology
- Oncology
Background:
- C3H 10T1/2 C18 (10T1/2) mouse embryo cells can differentiate into myogenic lineages.
- Understanding cellular determination's role in oncogenic transformation is crucial.
Purpose of the Study:
- To compare the oncogenic transformation susceptibility of myogenic derivatives versus parental 10T1/2 cells.
- To investigate the impact of cellular determination on chemical carcinogen and oncogene response.
Main Methods:
- Established three myogenic cell lines from 5-azacytidine-treated 10T1/2 cells.
- Exposed cells to 3-methylcholanthrene (chemical carcinogen) and activated human c-Ha-ras oncogene.
- Assessed transformation via soft agar growth, tumor formation in nude mice, and gene expression (c-Ha-ras, MyoD1).
Main Results:
- Myogenic derivatives showed resistance to 3-methylcholanthrene-induced transformation, unlike parental 10T1/2 cells.
- Both cell types transformed to tumorigenic phenotype after c-Ha-ras transfection.
- Transfected myogenic cells maintained MyoD1 expression and differentiated into striated muscle cells expressing myosin, even with multiple c-Ha-ras copies.
Conclusions:
- Cellular determination significantly alters susceptibility to chemical carcinogens.
- Activated c-Ha-ras oncogene can induce tumorigenesis in determined myogenic cells.
- c-Ha-ras expression does not inherently block myogenesis or terminal muscle differentiation.