Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Factors

Abstract

Although numerous epidemiological studies have shown that inorganic arsenicals 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 that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors , such as transforming growth factor (TGF)-␣, 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 phorbol acetate (TPA) , a marked increase in the number of skin papillomas occurred in Tg.AC mice , which carry the v-Haras oncogene , that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/ TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings , increases in granulocyte/ macrophage colony-stimulating factor (GM-CSF) and TGF-␣ mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment. Immunohistochemical staining localized TGF-␣ overexpression to the hair follicles. Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg.AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias 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. (Am J Pathol 1998, 153:1775-1785) Arsenic, a ubiquitous element, represents a human health concern when concentrated in the environment from natural or anthropogenic processes. Arsenic contamination of water supplies has resulted in a very high incidence of skin lesions and cancers in exposed populations from Taiwan, China, Eastern Europe, India, Southwestern United States, and Cental and South America. The U.S. Environmental Protection Agency (EPA) estimates that over 350,000 people in the U.S. consume drinking water containing over 50 g/L arsenic, the current EPA standard, 1 and there is significant regulatory pressure to lower the acceptable levels. Chronic exposure to inorganic arsenic in drinking water is most often associated with increased mortality from skin cancer, but recent studies have also linked arsenic exposure to neoplasias in internal organs, including the lung, liv...

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

“…The decrease of Nrf2 activation in response to high levels of oxidative stressors observed in As-TM cells, coupled with their acquired apoptotic resistance might increase the likelihood to acquire heritable oxidative DNA damage [7,9]. This may help explain the remarkable co-carcinogenic effects of arsenic and UV irradiation observed in mouse models of dermal carcinogenesis but the absence of activity for arsenic alone [3,4]. Our previous study indicated that exogenous GSH might markedly suppress hypochlorous acid-induced Nrf2 activation in mouse macrophages [50], suggesting the enhanced GSH levels in As-TM cells might be a critical factor for the weakened Nrf2 activation.…”

“…Arsenic is also carcinogenic in rodent models, producing liver, lung, ovary and adrenal tumors after transplacental exposure [2] and skin tumors in combination with ultraviolet (UV) irradiation or phorbol esters in mice [3,4]. However, arsenic alone does not appear to induce skin cancer in these mouse models [2][3][4], suggesting events associated with arsenic-induced dermal carcinogenesis may be distinct from other target tissues. Accumulating evidence suggests that oxidative stress occurs in response to arsenic exposure [5,6] and may be one factor in dermal arsenic carcinogenesis.…”

The role of Akt on Arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation

“…The mechanisms of these effects of arsenic on the development of diseases are not known. But previous studies indicated that alteration of cell proliferation contributes to its carcinogenicity [5]. On the other hand, arsenic has been used to treat cancers and it brings complete remission of acute promyeloid leukemia [6] .…”

Characterization of gene expression changes associated with MNNG, arsenic, or metal mixture treatment in human keratinocytes: application of cDNA microarray technology.

“…In transgenic Tg.AC mice, As acts as co-promoter during skin carcinogenesis in standard two-stage models (20). These studies have suggested that transforming growth factor-α (TGFα) and granulocyte/macrophage-colony stimulating factor may be useful biomarkers for As-associated carcinogenesis in keratinocytes; data from As-exposed human subjects support this hypothesis (20). It is likely, however, that the picture is much more complex than this and that the genes involved are more numerous.…”