Mechanisms of Carcinogenesis and Clinical Features of Asbestos-Associated Cancers

Mossman, Brooke T.; Kamp, David W.; Weitzman, Sigmund A.

doi:10.3109/07357909609018904

Cited by 175 publications

(90 citation statements)

References 74 publications

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“…Its pathogenesis has been postulated to be associated with the generation of free radicals (Kamp et al, 1992;Mossman et al, 1996). In contrast to previous observations, which have shown that MnSOD is usually low in malignant tumours (Oberley and Buettner, 1979;Oberley and Oberley, 1997), we have recently shown that the mRNA level, immunoreactive protein and specific activity of MnSOD are highly expressed in the tumour cells of malignant mesotheliomas when compared to healthy pleura or non-malignant transformed human mesothelial cells (Met5A) (Kinnula et al, 1996;Kahlos et al, 1998).…”

contrasting

confidence: 49%

Generation of reactive oxygen species by human mesothelioma cells

et al. 1999

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Malignant mesothelioma cells contain elevated levels of manganese superoxide dismutase (MnSOD) and are highly resistant to oxidants compared to non-malignant mesothelial cells. Since the level of cellular free radicals may be important for cell survival, we hypothesized that the increase of MnSOD in the mitochondria of mesothelioma cells may alter the free radical levels of these organelles. First, MnSOD activity was compared to the activities of two constitutive mitochondrial enzymes; MnSOD activity was 20 times higher in the mesothelioma cells than in the mesothelial cells, whereas the activities of citrate synthase and cytochrome c oxidase did not differ significantly in the two cell lines. This indicates that the activity of MnSOD per mitochondrion was increased in the mesothelioma cells. Superoxide production was assayed in the isolated mitochondria of these cells using lucigenin chemiluminescence. Mitochondrial superoxide levels were significantly lower (72%) in the mesothelioma cells compared to the mesothelial cells. Oxidant production in intact cells, assayed by fluorimetry using 2′,7′-dichlorodihydrofluorescein as a fluorescent probe, did not differ significantly between these cells. We conclude that mitochondrial superoxide levels are lower in mesothelioma cells compared to nonmalignant mesothelial cells, and that this difference may be explained by higher MnSOD activity in the mitochondria of these cells. Oxidant production was not different in these cells, which may be due to the previously observed increase in H 2 O 2 -scavenging mechanisms of mesothelioma cells. © 1999 Cancer Research Campaign

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confidence: 49%

Generation of reactive oxygen species by human mesothelioma cells

et al. 1999

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“…It is well known that malignant mesothelioma is caused by inhalation of asbestos [12,13]. In previous reports, it was shown that levels of oxidized pyrimidines and alkylated bases are strongly correlated with the length of occupational exposure to asbestos, and that an increase in the mutation frequency of lung DNA was induced by instillation with asbestos via the trachea [14,15].…”

Section: Malignant Mesothelioma and Antitumor Immunitymentioning

confidence: 99%

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases

Nishimura

Maeda

Kumagai-Τakei

et al. 2013

Environ Health Prev Med

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Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-b) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma.

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“…The pathogenesis of this disease is associated with exposure to asbestos fibres (Mossman et al, 1996). Recently, Simian virus-40 (SV-40) has been associated with this malignancy (Carbone et al, 1994).…”

mentioning

confidence: 99%

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

Tomasetti¹,

Rippo²,

Alleva

et al. 2004

Br J Cancer

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Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of a-tocopheryl succinate (a-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to a-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or a-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAILinduced apoptosis and its augmentation by a-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by a-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by a-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that a-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.

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Mechanisms of Carcinogenesis and Clinical Features of Asbestos-Associated Cancers

Cited by 175 publications

References 74 publications

Generation of reactive oxygen species by human mesothelioma cells

Generation of reactive oxygen species by human mesothelioma cells

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases

α-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells

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