The Cell and Molecular Biology of Nickel Compound–Induced Neoplastic Transformation and Carcinogenesis
This chapter briefly describes current knowledge on the occurrence of nickel and its ores and the chemistry and uses of nickel compounds.
It discusses the toxicology and carcinogenicity of specific insoluble nickel compounds in the occupational setting of nickel refining. The toxicology, cell transformation, and carcinogenicity induced by insoluble nickel compounds are then compared to those of soluble nickel compounds. One focus of the discussion is on the molecular mechanisms by which insoluble carcinogenic nickel compounds are taken up into cells by phagocytosis and then induce genotoxicity. This is thought to begin with nickel ion-induced generation of superoxide radicals, followed by generation of hydrogen peroxide and then by the nickel ion-induced generation of hydroxyl radicals from hydrogen peroxide (reviewed in [1, 2]). Nickel ion-generated hydrogen peroxide and nickel ion-generated hydroxyl radicals are believed to cause mutations in nickel ion-treated cells, plus micronuclei, chromosome aberrations, morphological and neoplastic transformation of cultured mammalian cells, and carcinogenesis in animals and in humans (reviewed in ). Carcinogenic, insoluble nickel compounds, such as crystalline nickel monosulfide, nickel subsulfide, and black and green nickel oxides, are phagocytosed by mammalian cells, which then generate intracellular Ni2+ ions [2, 3]. These intracellular Ni2+ ions cause chromosomal breakage, micronucleus formation, and amplification of the ect-2 proto-oncogene , which are genotoxic in C3H/10T1/2 mouse embryo cells, as shown in our laboratory (reviewed in [2, 4]). The intracellular Ni2+ ions generated by insoluble carcinogenic nickel compounds also cause silencing of tumor suppressor genes, such as the vitamin D receptor interacting protein #80 (DRIP80) gene and the β-centaurin-2 gene, and other genes such as the flavin adenine dinucleotide (FAD) synthetase gene , as shown in our laboratory, presumably by epigenetic mechanisms. In the laboratory of Professor Max Costa, evidence for nickel compound-induced epigenetic mechanisms in the process of nickel compound carcinogenesis has been demonstrated [6-8]. Hence, our hypotheses and working model of nickel compound carcinogenesis are that carcinogenic nickel compounds act by a combination of genotoxic and epigenetic mechanisms to induce morphological and neoplastic transformation of C3H/10T1/2 Cl 8 mouse embryo cells. These genotoxic and epigenetic mechanisms cause the loss of regulation of transcription and hence the differential expression of 144 genes between nontransformed C3H/10T1/2 Cl
8 mouse embryo cells on the one hand, and 3-methylcholanthrenetransformed and NiO-transformed and crystalline NiS-transformed C3H/10T1/2 cells on the other hand [2, 4, 5]. Our current working model is that each time a gene is amplified or mutated, this results in the further overexpression of an additional 9 genes. Our work to date found that 6 initial genes are overexpressed, leading to the overexpression of a further 54 genes. Further, 9 genes are underexpressed/not expressed in the transformed cells, leading to the lack of expression/lowered expression of a further 81 genes. This degradation in the control of expression of 144 genes in nickel compound-treated cells leads to the induction and maintenance of expression of morphological and neoplastic transformation. These processes are discussed in detail in the following text.