Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma

Our plain-English summary of Inflammation-Related IL1β/IL1R Signaling Promotes the Development of Asbestos-Induced Malignant Mesothelioma, by Y. Kadariya, C.W. Menges, J. Talarchek, et al (Cancer Prevention Research, 2016).

The study

• Authors: Y. Kadariya, C.W. Menges, J. Talarchek, K.Q. Cai, A.J. Klein-Szanto, R.A. Pietrofesa, M. Christofidou-Solomidou, M. Cheung, B.T. Mossman, A. Shukla, J.R. Testa
• Journal: Cancer Prevention Research
• Published: 2016;9(5):406-414
• Cited by: 70 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Exposure to asbestos is causally associated with the development of malignant mesothelioma, a cancer of cells lining the internal body cavities. Malignant mesothelioma is an aggressive cancer resistant to all current therapies. Once inhaled or ingested, asbestos causes inflammation in and around tissues that come in contact with these carcinogenic fibers. Recent studies suggest that inflammation is a major contributing factor in the development of many types of cancer, including malignant mesothelioma. The NALP3/NLRP3 inflammasome, including the component ASC, is thought to be an important mediator of inflammation in cells that sense extracellular insults, such as asbestos, and activate a signaling cascade resulting in release of mature IL1β and recruitment of inflammatory cells. To determine if inflammasome-mediated inflammation contributes to asbestos-induced malignant mesothelioma, we chronically exposed Asc-deficient mice and wild-type littermates to asbestos and evaluated differences in tumor incidence and latency. The Asc-deficient mice showed significantly delayed tumor onset and reduced malignant mesothelioma incidence compared with wild-type animals. We also tested whether inflammation-related release of IL1β contributes to tumor development in an accelerated mouse model of asbestos-induced malignant mesothelioma. Nf2(+/-);Cdkn2a(+/-) mice exposed to asbestos in the presence of anakinra, an IL1 receptor (IL1R) antagonist, showed a marked delay in the median time of malignant mesothelioma onset compared with similarly exposed mice given vehicle control (33.1 weeks vs. 22.6 weeks, respectively). Collectively, these studies provide evidence for a link between inflammation-related IL1β/IL1R signaling and the development of asbestos-induced malignant mesothelioma. Furthermore, these findings provide rationale for chemoprevention strategies targeting IL1β/IL1R signaling in high-risk, asbestos-exposed populations. Cancer Prev Res; 9(5); 406-14. ©2016 AACR.

©2016 American Association for Cancer Research.

In plain English

This was a laboratory study in genetically engineered mice testing whether inflammasome-driven inflammation contributes to asbestos-induced malignant mesothelioma (MM). Eighty-four mice (26 Asc+/+, 29 Asc+/-, 29 Asc-/-) received intraperitoneal crocidolite asbestos, 400 µg every 21 days for eight injections (3.2 mg total). Median percent disease-free time was 69.4 weeks for Asc+/- and 66.2 weeks for Asc-/- mice versus 61.6 weeks for wild-type littermates; MM incidence was 65% in Asc+/- and 55% in Asc-/- versus 80% in wild-type, significant for Asc-/- (p less than 0.05) but not Asc+/- (p less than 0.20). Three days after injection, plasma and peritoneal lavage IL-1β and IL-6 were lower in Asc+/- than wild-type mice; at three months post-exposure the authors found no detectable IL-1β difference between genotypes. In a second experiment, 32 asbestos-exposed Nf2+/-;Cdkn2a+/- mice per arm received the IL-1 receptor antagonist anakinra or vehicle; median percent disease-free time was 33.1 versus 22.6 weeks, though all mice eventually developed MM. The authors concluded these findings link IL-1β/IL-1R signaling to asbestos-induced MM development.

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: Animal carcinogenicity experiments in genetically engineered mice, with supporting in vitro work on human mesothelial cells
• Who was studied: 84 Asc-genotype mice (26 Asc+/+, 29 Asc+/-, 29 Asc-/-) on a C57BL/6 background, plus 32 Nf2+/-;Cdkn2a+/- mice per treatment arm; also HM3 normal human mesothelial cells in vitro
• Exposure: Intraperitoneal crocidolite asbestos (UICC grade): 400 µg every 21 days, eight injections (3.2 mg total) in Asc mice; 800 µg every 21 days, four injections (3.2 mg total) in Nf2+/-;Cdkn2a+/- mice, with or without anakinra 5 mg/kg
• Main results:
  • Median percent disease-free time was 69.4 weeks in Asc+/- mice and 66.2 weeks in Asc-/- mice, versus 61.6 weeks in asbestos-exposed wild-type mice
  • MM incidence was 65% in Asc+/- and 55% in Asc-/- mice versus 80% in wild-type; the difference was significant only for Asc-/- versus wild-type
  • In the figure summary, MM occurred in 21/26 wild-type and 19/29 Asc+/- mice, with the disease-free difference reported at p < 0.0001 and the incidence difference at p < 0.20
  • Most tumours were sarcomatoid: 14 of 21 (67%) in wild-type, 13 of 19 (68%) in Asc+/-, 12 of 16 (75%) in Asc-/- mice
  • Cytokines were measured in blood and peritoneal lavage fluid collected 3 days after asbestos or vehicle injection; IL-1β was lower in plasma and lavage fluid of Asc+/- than wild-type mice
  • IL-6 was lower in plasma and lavage fluid of unexposed and asbestos-injected Asc+/- mice than wild-type; TNFα did not differ significantly in unexposed mice but was lower in asbestos-exposed Asc+/- mice
  • At 3 months after exposure, the authors reported no detectable difference in IL-1β levels between genotypes
  • Asbestos-exposed Nf2+/-;Cdkn2a+/- mice given anakinra had a median percent disease-free time of 33.1 weeks versus 22.6 weeks for vehicle-treated mice
  • All mice in both arms of the anakinra experiment eventually developed MM
  • In HM3 human mesothelial cells, anakinra blocked IL-1β-stimulated activation of AKT, MAPK-ERK, mTOR-S6RP and JNK; tumours from anakinra-treated mice showed decreased P-AKT, P-ERK and P-JNK staining
• The authors' conclusion: The authors concluded that the inflammasome and IL-1β/IL-1R signaling contribute to asbestos-induced mesothelioma development, giving a rationale for chemoprevention targeting this pathway in chronically exposed groups
• Limitations the authors state:
  • Six Asc-/- mice developed peritonitis and had to be excluded from the disease-free comparisons, suggesting their immune systems were compromised
  • The authors state the genetic evidence from Asc-deficient mice was less striking than the pharmacological evidence, with only a modest decrease in overall MM incidence
  • All anakinra-treated mice eventually developed mesothelioma, so other cytokines or immune components may compensate
  • Asc deficiency did not prevent asbestos-induced mesothelioma

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: Inflammation, Malignant Mesothelioma, Carcinogenic, Latency, CDKN2A.

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