Silicosis and lung cancer: a fifty-year perspective.
The development of our studies on silica carcinogenesis and its mechanisms is reviewed. Starting from an analysis of the cellular reactions to silica in the pathogenesis of silicosis in the rat, followed by an analysis of the carcinogenic response to silica in the lungs of rats (but not in mice and hamsters), we went on to develop cellular models for culture and neoplastic transformation of rat alveolar epithelial cells. We studied the binding of silica to DNA, the generation of reactive oxygen species and the DNA damage mediated by hydroxyl radicals, showing marked differences among silica samples of varying purity. Then we investigated the role of peptides induced by silica in various cells, including cytokines and growth factors. Tumor necrosis factor (TNF)-alpha, which can cause activation of DNA transcription and is required for silica-induced fibrosis, was found to inhibit neoplastic transformation by quartz in cell cultures. Transforming growth factor (TGF)-beta was found to be produced in hyperplastic alveolar type II cells and to reach fibroblasts, macrophages and the connective tissue matrix adjacent to silicotic granulomas. Neuroendocrine cells and their peptides were found to be increased in alveolar and bronchiolar epithelia of silica lesions in rats, in contrast with mice and hamsters. Expression of adhesion molecules was found to be altered in silica-induced carcinogenesis and epithelial-mesenchymal transition was revealed by mesenchymal markers in the induced carcinomas. Promoter hypermethylation of adhesion genes in the induced carcinomas indicated a role for epigenetic mechanisms.
Saffiotti
Umberto
U
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
D000818:Animals; D002471:Cell Transformation, Neoplastic; D016207:Cytokines / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D051381:Rats; D012829:Silicosis / Q000150:complications* / Q000473:pathology; D013997:Time Factors
D016207:Cytokines; D006133:Growth Substances