Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors
Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors
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DOI：
10.1016/s1383-5742(97)00006-9
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发表时间：
1997-06-01
影响因子：
5.3
通讯作者：
Luster, MI
中科院分区：
文献类型：
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作者：
Germolec, DR;Spalding, J;Luster, MI
虽然大量流行病学研究表明无机砷是人类皮肤致癌物，但目前还没有公认的作用机制，也没有确定的动物模型进行研究。我们观察到，在低微摩尔浓度亚砷酸钠的存在下，培养的原代人表皮角质形成细胞中，角质形成细胞生长因子的mRNA转录和分泌增加，包括粒细胞巨噬细胞集落刺激因子（GM-CSF）和转化生长因子- α (tgf - α)以及促炎细胞因子肿瘤坏死因子- α (tnf - α)。在亚砷酸钠处理的角质细胞培养物中，细胞总数、c-myc表达和[H-3]胸苷的掺入这两个细胞增殖指标也有所升高。作为体内模型，我们在转基因TG中研究了砷对小鼠皮肤肿瘤发展的影响。携带v-Ha-ras癌基因的AC小鼠，可以作为皮肤致癌的遗传启动模型，在低剂量应用12- o -十四烷醇-13-乙酸酯（TPA）后，与对照饮用水相比，饮用砷的转基因小鼠皮肤乳头瘤的数量明显增加。砷处理的转基因小鼠未接受TPA或砷处理的野生型FVB/N小鼠均未发生乳头瘤，提示砷既不是肿瘤的启动剂也不是肿瘤的促进剂，而是一种增强剂。在转基因小鼠应用TPA后注射抗gm - csf抗体可减少乳头瘤的数量。与在人角质细胞培养中观察到的结果一致，与对照组相比，在砷处理小鼠的表皮中发现GM-CSF和tgf - α mRNA转录物在治疗6周内增加。这些结果表明，砷通过慢性刺激角质形成细胞衍生的生长因子来促进乳头状瘤的发展，这是以这种方式起作用的化学致癌物的第一个例子。这些研究表明，与TG结合的人角质细胞培养的体外研究。AC转基因小鼠可为研究环境化学物质的促肿瘤特性提供有益的模型。
Although numerous epidemiological studies have shown that inorganic arsenicals are human skin carcinogens, there is currently no accepted mechanism for its action or an established animal model for its study. We observed increased mRNA transcripts and secretion of keratinocyte growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-alpha (TGF-alpha) and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in primary human epidermal keratinocytes cultured in the presence of low micromolar concentrations of sodium arsenite. Total cell numbers, as well as c-myc expression and incorporation of [H-3]thymidine, both indicators of cell proliferation, were also elevated in keratinocyte cultures treated with sodium arsenite, As an in vivo model, the influence of arsenic on mouse skin tumor development was studied in transgenic TG.AC mice which carry the v-Ha-ras oncogene, and can serve as a genetically initiated model for skin carcinogenesis, Following low-dose application of 12-O-tetradecanoyl phorbol-13-acetate (TPA), a marked increase in the number of skin papillomas occurred in transgenic mice receiving arsenic in the drinking water as compared to control drinking water. Papillomas did not develop in arsenic-treated transgenic mice that had not received TPA or arsenic-treated wild-type FVB/N mice, suggesting that arsenic is neither a tumor initiator or promoter but rather an enhancer, Injection of anti-GM-CSF antibodies following application of TPA in transgenic mice reduced the number of papillomas. Consistent with that observed in human keratinocyte cultures, increases in GM-CSF and TGF-alpha mRNA transcripts were found within the epidermis of arsenic-treated mice when compared to controls within 6 weeks of treatment. These results suggest that arsenic enhances papilloma development via the chronic stimulation of keratinocyte-derived growth factors and represents the first example of a chemical carcinogen that acts in this manner. These studies suggest that in vitro studies with human keratinocyte cultures examined in conjunction with TG.AC transgenic mice can provide a useful model for examining the tumor enhancing properties of environmental chemicals.