Spontaneous and asbestos-induced transformation of mesothelial cells in vitro (original) (raw)
Related papers
Cancer Research, 1995
Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regard ing the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor a (TGF-a) to act as an autocrine growth factor in trans formed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-a. Expression of TGF-a transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-a inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing antibody that rec ognized TGF-a secreted by the asbestos-transformed cells was able to inhibit the growth of these cells. Taken together, these data indicate that TGF-a acts as an autocrine growth factor for asbestos-transformed rat mesothelial cells. Therefore, in asbestos-transformed mesothelial cells, altered production and responsiveness to TGF-a distinguish these cells from spontaneously transformed mesothelial cells. These data suggest that differences in mesothelioma etiology may be reflected in differences in the molecular alterations present in these tumors.
1995
Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regard ing the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor a (TGF-a) to act as an autocrine growth factor in trans formed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-a. Expression of TGF-a transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-a inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing antibody that rec
Cancer research, 1995
Although the association between asbestos exposure and mesothelioma development has been established for decades, very little is known regarding the molecular mechanism(s) by which asbestos fibers induce this disease. In this series of experiments, the potential for transforming growth factor alpha (TGF-alpha) to act as an autocrine growth factor in transformed mesothelial cells was examined in rats, a model system frequently used to assess the tumorigenic potential of fibrous particulates. Both asbestos-transformed cells and spontaneously transformed cells expressed functional EGF receptors, although only the asbestos-transformed cells expressed TGF-alpha. Expression of TGF-alpha transcripts was correlated with secretion of picogram amounts of growth factor into conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-alpha inhibited the growth of spontaneously transformed mesothelial cells, it stimulated the growth of asbestos-transformed cells. Neutralizing ...
Environmental and Molecular Mutagenesis, 1995
We report the effects of chrysotile and crocidolite asbestos, and glass and rock wool fibers (man-made vitreous fibers, MMVF) on the induction of binucleate cells in vitro. The response of human mesothelial cells (target cells in fiber carcinogenesis) and rodent cells was compared. Human primary mesothelial cells, MeT-5A cells (an immortalized human mesothelial cell line), and rat liver epithelial (RLE) cells were exposed to asbestos and MMVF samples of similar size range. Milled glass wool, milled rock wool, and titanium dioxide were used as non-fibrous particle controls. All four fiber types caused statistically significant increases in the amount of binucleate cells in human primary mesothelial cells and MeT-5A cells (in the dose range OS-5.0 pg/ cm'). Chrysotile and crocidolite asbestos were more effective (1.3-3.0-fold increases) than thin glass wool and thin rock wool fibers (1.3-2.2fold increases). However, when the fiber doses were expressed as the number of fibers per culture area, the asbestos and MMVF appeared equally effective in human mesothelial cells. In RLE cells, chrysotile was the most potent inducer of binucleation (2.9-5.0-fold increases), but the response of the RLE cells to crocidolite, thin glass wool, and thin rock wool fibers was similar to the response of the human mesothelial cells. No statistically significant increases in the number of bior multinucleote cells were observed in human primary mesothelial cells or RLE cells exposed to the non-fibrous dusts. In MeT-5A cells exposed to 5 pg/cm' of milled glass wool and milled rock wool, as well as in cultures exposed to 2 and 5 pg/crn' of Ti02, significant increases were, however, observed. Our results show that rodent cells respond differently to mineral fibers than human cells. The results also add evidence to the suggested importance of disturbed cell division in fiber carcinogenesis.
Pathogenesis of experimentally induced asbestos mesothelioma in rats
Cancer Letters, 1998
Fragments of parietal and visceral pleura were studied by total ®lms preparation, light microscopy and SEM at different times after intrapleural injection of asbestos in Wistar rats. Pleural rat mesothelium in histological slices consists normally of one layer of oblong cells. By SEM the cells are¯at and coated with microvilli of different lengths. In total ®lms the parietal mesothelium was composed of large polygonal cells covering intercostal spaces and small cells covering spaces over the ribs. In¯ammatory reaction and permanent pathological regenerative processes were observed in the mesothelium during 24 months after inoculation of asbestos ®bres. Different lesions which we regarded as preneoplastic or premesotheliomatous were observed against the background of or without these processes. They were diffuse irregular hyperplasia and proliferation of epithelium-like or ®broblast-like cells and focal nodous proliferates composed of such cells with various morphological structures. The number of thymidine-labelled cells was signi®cantly more inside the proliferates than in the surrounding tissue. They were con®rmed by SEM and histological slices of the same ®elds. Chronic pathological regeneration of pleural mesothelium could be the background against which preneoplastic lesions and mesotheliomas develop easily.
Mechanisms of asbestos-induced carcinogenesis
2011
Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows:
American Journal of Respiratory Cell and Molecular Biology, 1997
The control of DNA integrity in mammalian cells is important to maintain the cell homeostasis and prevent neoplastic transformation. Control of cell division and cell death permits repair or elimination of damaged cells. Since asbestos fibers can produce DNA damage, chromosome alterations and apoptosis in several sorts of cells, including mesothelial cells, it was interesting to investigate cell cycle disturbances in rat pleural mesothelial cells (RPMC) treated with asbestos fibers. Cell cycle analyses were performed in RPMC exposed to crocidolite (10 and 20 g/cm 2) and chrysotile (5 and 10 g/cm 2) for different times (4 to 48 h). Both fiber types entailed a G2/M accumulation in agreement with a delay in the mitosis course. Chrysotile fibers produced a G0/G1 accumulation associated with a time-dependent p53 and p21 expression. Crocidolite exposure resulted in a delay in the G1/S transition paralleling a low rate of p53 expression. These results are in agreement with a DNA damaging potential of asbestos fibers since similar results were found following RPMC exposure to ␥ rays. In asbestos-treated RPMC, a low rate of apoptosis was found suggesting that RPMC may follow a DNA repair pathway that could contribute to the formation of DNA lesions. In addition, the cell cycle disturbances at the G2/M checkpoint suggest that genetically altered cells have progressed through the cycle and support the already published findings on the ability of asbestos fibers to impair cell division. Levresse, V., A. Renier, J. Fleury-Feith, F. Levy, S. Moritz, C. Vivo, Y. Pilatte, and M.-C. Jaurand. 1997. Analysis of cell cycle disruptions in cultures of rat pleural mesothelial cells exposed to asbestos fibers. Am. J. Respir. Cell Mol. Biol. 17:660-671.
Erionite and asbestos differently cause transformation of human mesothelial cells
… journal of cancer, 2007
Malignant Mesothelioma (MMe) is an aggressive tumor associated with environmental or occupational exposure to asbestos fibers. Erionite is a fibrous Zeolite, morphologically similar to asbestos and assumed even more carcinogenic. Onset and progression of MMe has been suggested as the result of the cooperation between asbestos and other cofactors, like SV40 virus infection. Nevertheless, several cases of MMe were associated with environmental exposure to Erionite in Turkey, where SV40 was never isolated in MMe specimens. We show here that Erionite is poorly cytotoxic, induces proliferative signals and high growth rate in Human Mesothelial Cells (HMC). Long term exposure to Erionite, but not to Asbestos fibers transforms HMC in vitro, regardless the presence of SV40 sequences, leading to foci formation in cultured monolayers. Cells derived from foci display constitutive activation of Akt, NF-kB and Erk1/2, show prolonged survival and a deregulated cell cycle, involving cyclin D1 and E overexpression. Our results reveal that Erionite is able per se to turn HMC into transformed highly proliferating cells and disclose the carcinogenic properties of Erionite prompting for a careful evaluation of environmental exposure to these fibers.