Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production
Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production
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DOI：
10.1093/carcin/bgt267
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发表时间：
2014-01-01
期刊：
影响因子：
4.7
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Chew, Shan Hwu;Okazaki, Yasumasa;Toyokuni, Shinya
像许多其他人类癌症一样，恶性间皮瘤的发展与慢性炎症密切相关。巨噬细胞和间皮细胞在石棉暴露引起的炎症反应中起着关键作用。在这里，我们表明，脂肪细胞也可以通过失调的脂肪细胞因子的产生来促进石棉引起的炎症。3T3-L1前脂肪细胞在使用前分化为成熟脂肪细胞。这些细胞吸收石棉纤维(温石棉、青石棉和铁石棉)，但比巨噬细胞和间皮细胞更能抵抗石棉引起的损伤。表达芯片分析和逆转录聚合酶链式反应显示，脂肪细胞对石棉暴露的直接反应是促炎脂肪细胞因子[如单核细胞趋化蛋白-1(MCP-1)]的产生增加，而抗炎脂肪细胞因子(如脂联素)的产生受到抑制。在小鼠附睾脂肪垫内注射石棉纤维后，证实了这一点。这种失调的脂肪细胞因子的产生有利于促炎环境的建立。此外，MCP-1对MET-5A间皮细胞的生长有微弱的促进作用，对Y-Meso-8A和Y-Meso-8D间皮瘤细胞的创面愈合有明显的促进作用。我们的结果表明，脂肪细胞因子水平的增加，如单核细胞趋化蛋白-1，可能通过促进炎症细胞的募集以及对间皮细胞和间皮瘤细胞的直接生长和迁移刺激作用来促进间皮癌的发生。综上所述，我们的发现支持脂肪细胞在石棉诱导的间皮癌变中具有潜在的促癌作用。
Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcriptionPCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.