NEOPLASTIC TRANSFORMATION BY CRYSTALLINE SILICA AND OTHER MINERALS

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Neoplastic transformation was induced by quartz particles in the fetal rat lung alveolar epithelial cell line, fetal rat lung epithelial (FRLE), treated in serum-free MEM medium for 24 hr and then fed with MEM/10% fetal bovine serum. Three experiments showed the induction by quartz of morphologically altered colonies or foci of epithelial cells. These were subcultured and inoculated in nude mice, in which they gave rise to carcinomas. The original morphological transformant yielded colonies in soft agar that were also tumorigenic in nude mice. Cells subcultured from the tumors in nude mice were, in turn, also tumorigenic. Neoplastic transformation was obtained with single exposures to quartz dust at doses ranging from 12.5 to 100 microg/cm2. This novel finding, showing that quartz can induce neoplastic transformation in rat lung alveolar epithelial cells, provides evidence that quartz particles can transform target epithelial cells directly, without mediation by mesenchymal cells. Cells from nude mouse tumors derived from quartz-transformed cells (QTT- T1C) were growth-inhibited by TGF-beta1 and TGF-beta2, as were the parent FRLE cells, whereas cells from nude mouse tumors derived from FRLE cells transformed by a mutated ras plasmid (RT-T1) were relatively unaffected. TGF-beta1 and TGF-beta2 mRNAs were expressed at higher levels in QTT-T1C cells than in FRLE and RT-T1C cells. Carcinomas in nude mice derived from QTT and RT cells did not express TGF-beta latency-associated protein, in analogy with carcinomas induced in rats by quartz, suggesting a posttranscriptional regulation. The tobacco-specific nitrosamine, NNK, was found to induce marked dose-dependent cytotoxicity in FRLE cells, indicating that FRLE cells can metabolically activate NNK and are therefore appropriate for studies on combined effects of quartz and NNK. The role of associated minerals on the toxicity and transforming activity of quartz was confirmed by new results using the BALB/3T3/A31-1-1 cell line. Hematite and anatase were nontoxic and nontransforming and inhibited both toxicity and transformation by quartz. Rutile, which was more toxic than quartz, but nontransforming, enhanced quartz toxicity, but not its transforming activity.