Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production

Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflamma-tory 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 adi-pocytokine production. 3T3-L1 preadipocytes were differenti-ated 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 fol-lowed by reverse transcription–PCR revealed that adipocytes respond directly to asbestos exposure with an increased pro-duction of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is sup-pressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregu-lated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 margin-ally 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 carcino-genesis 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 find-ings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.Introduction