NEOPLASTIC TRANSFORMATION BY CRYSTALLINE SILICA AND OTHER MINERALS

石英颗粒在胎儿体内诱发的肿瘤转化 大鼠肺泡上皮细胞系，胎鼠肺上皮(FRLE)， 在无血清MEM培养液中处理24小时，然后饲喂MEM/10% 胎牛血清。三个实验表明，石英诱导的 上皮细胞的形态改变的菌落或病灶。这些都是 继代培养并接种于裸鼠体内，在其中产生了 癌症。最初的形态转化子在 软琼脂，在裸鼠体内也有致瘤作用。传代培养的细胞 而裸鼠体内的肿瘤也具有致瘤性。肿瘤 单次暴露于剂量的石英尘即可获得转化。 从12.5微克/平方厘米到100微克/平方厘米。这一新发现表明， 石英可诱导大鼠肺泡癌变 上皮细胞，提供了石英颗粒可以转化为 直接靶向上皮细胞，不需要间充质细胞的参与。 裸鼠肿瘤细胞来源于石英转化细胞(QTT-1) T1C)的生长受到转化生长因子β1和转化生长因子β2的抑制，亲本也是如此 FRLE细胞，而裸鼠肿瘤细胞来源于FRLE细胞 用突变的ras质粒(RT-T1)转化的菌株相对不受影响。 转化生长因子-β1和转化生长因子-β2的mRNAs在QTT-T1C中高水平表达 细胞数高于FRLE和RT-T1C细胞。裸鼠皮下移植瘤 QTT和RT细胞不表达转化生长因子-β潜伏期相关 蛋白质，类似于石英诱发的大鼠癌症，提示 转录后调控。烟草特有的亚硝胺，NNK， 被发现在FRLE细胞中诱导显著的剂量依赖性细胞毒性， 这表明FRLE细胞可以代谢激活NNK，并且是 因此，适合于研究石英和NNK的联合效应。 伴生矿物在毒性和转化活性中的作用 利用BALB/3T3/A31-1-1细胞的新结果证实了石英的存在 排队。赤铁矿和锐钛矿是无毒和不转化的 石英对其毒性和转化均有抑制作用。金红石，这是 比石英毒性更大，但不会转化，增强了石英毒性， 但不是它的转型活动。

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.