title: Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production.
abstract: 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 transcription-PCR 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.
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shan Hwu
authors.initials: SH
authors.lastname: Chew
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nagai
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Misawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Akatsuka
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Michio
authors.initials: M
authors.lastname: Noguchi
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D054392:Adipokines / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001194:Asbestos / Q000493:pharmacokinetics / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D054392:Adipokines; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D001194:Asbestos