Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma

Our plain-English summary of Chronic Inflammation, Oxidative Stress and Metabolic Plasticity: Three Players Driving the Pro-Tumorigenic Microenvironment in Malignant Mesothelioma, by I. Fiorilla, S. Martinotti, A.M. Todesco, et al (Cells, 2023).

The study

• Authors: I. Fiorilla, S. Martinotti, A.M. Todesco, G. Bonsignore, M. Cavaletto, M. Patrone, E. Ranzato, V. Audrito
• Journal: Cells
• Published: 2023;12(16)
• Type of article: Review
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells' transformation. Chronic inflammation supported by "frustrated" macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells' features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor-host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM.

In plain English

This article is a review, not a new study. The authors summarized published laboratory, animal and clinical research on how malignant pleural mesothelioma (MPM) develops and progresses after asbestos exposure. They focused on three processes: chronic inflammation, oxidative stress, and changes in how tumor and immune cells use energy (metabolism). The review described research indicating that macrophages cannot fully engulf long asbestos fibers. It described this "frustrated phagocytosis" as prompting inflammatory cells to release reactive oxygen species and pro-inflammatory cytokines. Separately, it described stressed macrophages and mesothelial cells dying and releasing a protein called HMGB1. Among the other studies it cited, one reported that human mesothelial cells exposed to chrysotile in the laboratory underwent changes linked to TGF-beta1. Another reported high blood HMGB1 levels in people exposed to asbestos and in mesothelioma patients. The authors noted conflicting results on the role of IL-6 and very little information on the adenosine pathway in MPM. The authors concluded that these interactions create pro-tumoral and immunosuppressive conditions, and that new combination therapies and biomarkers are needed.

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: Narrative review of published research; no new data were collected
• Who was studied: No study population of its own; the review covered published laboratory, animal and clinical research on malignant pleural mesothelioma (MPM)
• Exposure: Asbestos fibers in general, described as the main risk factor for MPM; one cited laboratory study used chrysotile
• Main results:
  • The review described frustrated phagocytosis of long asbestos fibers as prompting the surrounding inflammatory cells to release free radicals such as reactive oxygen species.
  • The review described stressed macrophages and mesothelial cells undergoing necrosis and releasing the protein HMGB1.
  • The review described two ways, reported in earlier research, by which asbestos fibers can generate reactive oxygen species. The first is the iron content of the fibers. The second is over-activation of inflammatory immune cells.
  • The review cited a study reporting high blood levels of HMGB1 in people exposed to asbestos and in mesothelioma patients.
  • The review cited a laboratory study (Turini et al.) in which human mesothelial cells (MeT-5A) exposed to chrysotile asbestos switched on an epithelial-to-mesenchymal transition program, which the review described as mediated by over-expression of TGF-beta1.
  • The review cited a trial of fresolimumab, an anti-TGF-beta antibody, in patients with advanced mesothelioma. It reported no evident radiographic responses and a short median progression time of 1.4 months, with 10 patients progressing after only two cycles. The review does not give the total number of patients in that trial.
  • The review cited a genomic analysis of 74 mesothelioma tumors that found TGF-beta1 mRNA expression was correlated with the worst patient prognoses.
  • The review reported that the studies it covered gave conflicting results on whether IL-6 acts as a growth factor for mesothelioma cells.
  • The review cited research reporting increased extracellular lactate in cell culture media from MPM primary cells derived from patients carrying germline BAP1 mutations.
• The authors' conclusion: The authors concluded that interactions between mesothelioma, stromal and immune cells, together with soluble factors and metabolic changes, create pro-tumoral and immunosuppressive conditions that favor disease progression. They also concluded that the efficacy of current approaches such as immunotherapy remains to be confirmed, and that new combination therapies and biomarkers are needed.
• Limitations the authors state:
  • The authors stated that the exact molecular mechanisms by which asbestos causes MPM are complex and not fully known.
  • The authors stated that very little information exists on the role of the adenosine pathway in MPM.
  • The authors noted significant differences in tumors within and between patients.

Topics

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

Medical terms in this study, explained in our Lexicon: Chronic Inflammation, Oxidative Stress, Malignant Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Mesothelioma, Reactive Oxygen Species (ROS), Mesothelial Cells.

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