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

Our plain-English summary of Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production, by S.H. Chew, Y. Okazaki, H. Nagai, et al (Carcinogenesis, 2014).

The study

• Authors: S.H. Chew, Y. Okazaki, H. Nagai, N. Misawa, S. Akatsuka, K. Yamashita, L. Jiang, Y. Yamashita, M. Noguchi, K. Hosoda, Y. Sekido, T. Takahashi, S. Toyokuni
• Journal: Carcinogenesis
• Published: 2014;35(1):164-72
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study used cultured cells and mice. The authors exposed mature mouse fat cells (adipocytes) to chrysotile, crocidolite and amosite asbestos. The fat cells took up all three fiber types. At the one concentration and 72-hour period tested, the fibers showed no toxic effect on these cells, unlike mesothelial cells and macrophages. Fat cells exposed to chrysotile or crocidolite released more of the inflammatory signal MCP-1: 900.7 pg/ml in controls, 3116.5 pg/ml with chrysotile and 3455.9 pg/ml with crocidolite. Amosite showed no apparent change. Male mice received one injection of 2.5 mg chrysotile or crocidolite into the abdominal cavity. After 3 days, their epididymal fat showed higher MCP-1 gene activity and lower adiponectin, an anti-inflammatory signal; the adiponectin drop was significant with chrysotile. Fluid from asbestos-treated fat cells drew more macrophages in a migration test. Added MCP-1 had a marginal, not statistically significant effect on mesothelial cell growth and no effect on their movement. It did increase movement of two human mesothelioma cell lines. The authors suggested these fat-cell signals might help promote malignant mesothelioma and called for long-term studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: cell-culture experiments plus a short-term animal (mouse) experiment
• Who was studied: Mouse 3T3-L1 preadipocytes differentiated into mature adipocytes; human MeT-5A mesothelial cells; RAW264.7 macrophages; Y-MESO-8A and Y-MESO-8D human mesothelioma cell lines (from one Japanese patient with malignant pleural mesothelioma); 8-week-old male ddY mice (n = 6 per group for gene measurements)
• Exposure: UICC chrysotile A, crocidolite and amosite at 10 μg/cm2 in culture (72 h for viability testing); tangled carbon nanotubes as a comparison particle; in mice, a single intraperitoneal injection of 2.5 mg chrysotile or crocidolite (saline control), with fat harvested after 3 days
• Main results:
  • Cultured adipocytes took up all three asbestos types
  • In a viability assay at 10 μg/cm2 for 72 h, no cytotoxic effect of asbestos was observed on adipocytes, in contrast to mesothelial cells and macrophages
  • MCP-1 secretion by cultured adipocytes: control 900.7 pg/ml, chrysotile-treated 3116.5 pg/ml, crocidolite-treated 3455.9 pg/ml (P at or below 0.005)
  • Amosite-treated adipocytes showed no apparent change in MCP-1
  • In mice injected with asbestos, MCP-1 and Prl2c5 mRNA were upregulated in epididymal fat
  • In mouse fat, adiponectin suppression was more apparent than in cultured cells and was significant in chrysotile-injected mice; leptin was significantly down and IL-6 significantly up
  • Conditioned media from asbestos-treated adipocytes increased macrophage migration
  • MCP-1 had a marginal but not significant effect on MeT-5A mesothelial cell proliferation
  • MCP-1 had no effect on MeT-5A migration
  • MCP-1 promoted migration of the Y-MESO-8A and Y-MESO-8D mesothelioma cells
  • The authors found chrysotile appeared the most inflammogenic of the three fiber types
• The authors' conclusion: The authors concluded that asbestos-induced adipocytokines might act locally to stimulate mesothelial cells and thus promote the development of malignant mesothelioma
• Limitations the authors state:
  • A long-term study is needed to assess whether the observed changes are long-term effects
  • More detailed studies are needed on the roles of the various dysregulated adipocytokines
  • PAI-1 results disagreed between cell and mouse experiments

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Mesothelioma, Macrophage, Mesothelial Cells, Asbestos Exposure, Inflammation, Chrysotile, Crocidolite.

Related studies

• Mesothelial cell differentiation into osteoblast- and adipocyte-like cells — S.M. Lansley, R.G. Searles, et al. (2011)
• Ferroptosis-dependent extracellular vesicles from macrophage contribute to asbestos-induced mesothelial carcinogenesis through loading ferritin — F. Ito, K. Kato, et al. (2021)
• Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis — L. Jiang, S.H. Chew, et al. (2016)
• Global overexpression of divalent metal transporter 1 delays crocidolite-induced mesothelial carcinogenesis in male mice — S. Funahashi, Y. Okazaki, et al. (2018)
• Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats — H. Nagai, Y. Okazaki, et al. (2013)
• Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis — D. Aierken, Y. Okazaki, et al. (2014)

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