Transforming growth factor beta expression and transformation of rat lung epithelial cells by crystalline silica (quartz)

Abstract

Crystalline silica (quartz) induces silicosis and associated peripheral lung carcinomas in rats. The role and pattern of expression of transforming growth factor (TGF)-beta1/beta2 mRNA transcripts were investigated in the fetal rat lung epithelial cell line FRLE, its neoplastic transformants and derived tumors in athymic nude mice. FRLE cells, treated with 100 microgram/cm2 of quartz in serum-free medium, gave rise to phenotypically altered, tumorigenic cells. Quartz-treated, transformed and tumorigenic cells, subcultured directly (QTT-C1) or after growth in soft agar (QTT-C2), formed tumors in athymic nude mice (QTT-T1). Cells subcultured from the tumors (QTT-T1C) were also tumorigenic in nude mice (QTT-T2). QTT-T1 and QTT-T2 tumors were poorly differentiated carcinomas with variable amounts of extracellular matrix-associated TGF-beta1 and desmoplasia. For comparison, a tumorigenic cell line derived from FRLE cells transformed with a mutated K-ras plasmid (RT-C1) and cells subcultured from a corresponding nude mouse tumor (RT-T1) and designated RT-T1C were used. Whereas TGF-beta1 and TGF-beta2 inhibited the growth of QTT-T1C and FRLE cells in a dose-dependent fashion, RT-T1C cells, containing an activated ras gene, were relatively unaffected. TGF-beta1 and TGF-beta2 mRNAs were expressed at higher levels in QTT-T1C cells than in FRLE and TR-T1C cells, and there was an increase in TGF-beta type II receptor (TGR-betaR) mRNA expression in QTT-T1C and RT-T1C cells compared to FRLE cells. Carcinomas in nude mice derived from QTT and RT cells and silicosis-associated lung carcinomas induced in rats by intra-tracheal quartz did not express either active or latent forms of TGF-beta1 protein on immunohistochemistry. The disparity between TGF-beta1 mRNA and TGF-beta1 protein expression in QTT tumors may be due to post-transcriptional regulation of TGF-beta1.

In vitro comet and micronucleus assays do not predict morphological transforming effects of silica particles in Syrian Hamster Embryo cells

“…In the present work, we have shown that crystallized silica (Chd and Min-U-Sil) was able to induce transformed SHE colonies in a dose-dependent manner after seven days of treatment. Our results are in agreement with previous transformation studies on quartz [18], [21], [22], [23] and [24]. Hesterberg and Barrett [21] showed that two quartz samples induced a concentration-dependent increase in TF, and both of these samples were less potent than asbestos fibres.…”

Altered expression of adhesion molecules and epithelial–mesenchymal transition in silica-induced rat lung carcinogenesis

“…[69][70][71][72][73] The role of growth factors and cytokines in the pathogenesis of silica-induced lung carcinogenesis has been the object of earlier studies. [20][21][22][74][75][76][77] It was shown that hyperplastic type II cells present in this model are sites of active production and secretion of TGF-b1. 21,76 In rat alveolar cells in culture, silica treatment induced a dramatic secretion of TGF-b1.…”

“…21,76 In rat alveolar cells in culture, silica treatment induced a dramatic secretion of TGF-b1. 77 These data raise the possibility that TGF-b, and other growth factors secreted by the preneoplastic and neoplastic cells, could play a role in inducing the EMT observed in our model.…”

Hyperplasia of Alveolar Neuroendocrine Cells in Rat Lung Carcinogenesis by Silica with Selective Expression of Proadrenomedullin-Derived Peptides and Amidating Enzymes

“…The NE cell hyperplasia in the rat-the species of choice for silica carcinogenesis-and its possible role in stimulating cell proliferation in the adjacent epithelia represents a further hypothetical mechanism. These species differences may be related to other differences in the inflammatory cell response to silica (Driscoll et al, 1996;Schimmelpfeng and Seidel, 1991) and to the role of growth factors such as TGF-␤ and TNF-␣ (Saffiotti, 1993;Williams et al, 1996).…”