TRANSFORMING GROWTH-FACTOR-BETA EXPRESSION AND TRANSFORMATION OF RAT LUNG EPITHELIAL-CELLS BY CRYSTALLINE SILICA (QUARTZ)

Crystalline silica (quartz) induces silicosis and associated periphera l lung carcinomas in rats. The role and pattern of expression of trans forming growth factor (TGF)-beta 1/beta 2 mRNA transcripts were invest igated in the fetal rat lung epithelial cell line FRLE, its neoplastic transformants and derived tumors in athymic nude mice. FRLE cells, tr eated with 100 mu g/cm(2) of quartz in serum-free medium, gave rise to phenotypically altered, tumorigenic cells. Quartz-treated, transforme d and tumorigenic cells, subcultured directly (QTT-C1) or after growth in soft agar (QTT-C2), formed tumors in athymic nude mice (QTT-T1). C ells subcultured from the tumors (QTT-T1C) were also tumorigenic in nu de mice (QTT-T2). QTT-T1 and QTT-T2 tumors were poorly differentiated carcinomas with variable amounts of extracellular matrix-associated TG F-beta 1 and desmoplasia. For comparison, a tumorigenic cell line deri ved from FRLE cells transformed with a mutated K-ras plasmid (RT-C1) a nd cells subcultured from a corresponding nude mouse tumor (RT-T1) and designated RT-T1C were used. Whereas TGF-beta 1 and TGF-beta 2 inhibi ted the growth of QTT-TIC and FRLE cells in a dose-dependent fashion, RT-T1C cells, containing an activated ros gene, were relatively unaffe cted. TGF-beta 1 and TGF-beta 2 mRNAs were expressed at higher levels in QTT-T1C cells than in FRLE and RT-TIC cells, and there was an incre ase in TGF-beta type II receptor (TGF-beta R) mRNA expression in QTT-T 1C and RT-T1C cells compared to FRLE cells. Carcinomas in nude mice de rived from QTT and RT cells and silicosis-associated lung carcinomas i nduced in rats by intra-tracheal quartz did not express either active or latent forms of TGF-beta 1 protein on immunohistochemistry. The dis parity between TGF-beta 1 mRNA and TGF-beta 1 protein expression in QT T tumors may be due to post-transcriptional regulation of TGF-beta 1. (C) 1996 Wiley-Liss, Inc.