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Reversible transformation by v-sis: a model cell line for analysis of transformation by antisense methods
P M Carpenter1, M Mercola, D Mercola
1Department of Pathology, University of California, San Diego, La Jolla 92093.
Abstract:
Cellular homologs of v-sis are implicated in numerous human tumor types (Eva et al., 1982; Betsholtz et al., 1984; Johnson et al., 1985; Bronzert et al., 1987; Igarashi et al., 1987; Nister et al., 1988a,b; Versnel et al., 1988; Matsui et al., 1989), but whether tumor growth is maintained by sis expression alone or requires additional changes is unknown. To distinguish these possibilities, we studied reversible transformation of NIH-3T3 cells bearing an inducible v-sis construction. Cells subcultured from 10 of 18 tumors, all less than 0.1 gram and less than or equal to 21 days in age, reverted to a normal phenotype by four criteria, but again exhibited transformation upon induction. Thus, activation of the v-sis autocrine loop alone is sufficient for initiation of tumors. Cells from the remaining and larger, 0.5 +/- 0.7 gram, tumors did not revert by any criteria. This suggests that subsequent tumor growth is maintained by acquisition of irreversible change(s) that occurs at high frequency in vivo.
Insights
Activation of the v-sis gene alone can initiate tumor growth. However, sustained tumor expansion requires additional genetic alterations, suggesting a multi-step cancer progression model.
Area of Science:
- Oncogenesis
- Molecular Biology
- Cellular Transformation
Background:
- Cellular homologs of the viral gene v-sis are frequently found in human tumors.
- It remains unclear if v-sis expression alone drives tumor growth or if other genetic changes are necessary.
Purpose of the Study:
- To investigate whether v-sis activation is sufficient for tumor initiation and sustained growth.
- To differentiate between single-step (v-sis activation) and multi-step processes in tumor development.
Main Methods:
- Utilized NIH-3T3 cells engineered with an inducible v-sis construct.
- Studied the reversibility of cellular transformation in tumors of varying sizes and ages.
- Assessed phenotypic reversion and re-transformation upon v-sis induction.
Main Results:
- Early, small tumors ( < 0.1g, ≤ 21 days) derived from inducible v-sis cells showed reversible transformation, indicating v-sis activation alone is sufficient for initiation.
- Larger, established tumors (0.5 ± 0.7g) did not revert, suggesting the acquisition of irreversible changes.
- High-frequency in vivo changes appear necessary for sustained tumor growth beyond initial stages.
Conclusions:
- The v-sis autocrine loop is sufficient to initiate tumor formation.
- Subsequent tumor progression and sustained growth depend on the accumulation of additional, irreversible genetic alterations.