Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors

Although numerous epidemiological studies have shown that inorganic arsenic als cause skin cancers and hyperkeratoses in humans, there are currently no established mechanisms for their action or animal models, previous studies in our laboratory using primary human keratinocyte cultures demonstrated t hat micromolar concentrations of inorganic arsenite increased cell prolifer ation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth fact ors, such as transforming growth factor (TGF)-alpha, promote the formation of skin tumors, we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus, the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl p horbol acetate (TPA), a marked increase in the number of skin pap illomas o ccurred in Tg,AC mice, which carry the v-Ha-ras oncogene, that received ars enic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not re ceive TPA or arsenic/TPA-treated wild-type FVB/N mice. Consistent with earl ier in vitro findings, increases in granulocyte/macrophage colony-stimulati ng factor (GM-CSF) and TGF-alpha mRNA transcripts were found in the epiderm is at clinically normal sites within 10 weeks after arsenic treatment, Immu nohistochemical staining localized TGF-alpha overexpression to the hair fol licles, Injection of neutralizing antibodies to GM-CSF after TPA applicatio n reduced the number of papillomas in Tg,AC mice. Analysis of gene expressi on in samples of skin lesions obtained from humans chronically exposed to a rsenic via their drinking water also showed similar alterations in growth f actor expression. Although confirmation will be required in nontransgenic m ice, these results suggest that arsenic enhances development of skin neopla sias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter.