Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases

Our plain-English summary of Fibrosis in Mesothelioma: Potential Role of Lysyl Oxidases, by L. Perryman, S.G. Gray (Cancers, 2022).

The study

• Authors: L. Perryman, S.G. Gray
• Journal: Cancers
• Published: 2022;14(4)
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immunotherapies (such as checkpoint inhibitors) and standard chemotherapies (such as cisplatin) have limitations in the successful treatment of malignant pleural mesothelioma (MPM). Fibrosis is the accumulation of collagen in the extracellular matrix (ECM) of tissues, making them denser than that of healthy tissues and thereby affecting drug delivery and immune cell infiltration. Moreover, fibrosis severely affects the patient's breathing and quality of life. The production of collagen and its assembly is highly regulated by various enzymes such as lysyl oxidases. Many solid tumors aberrantly express the family of lysyl oxidases (LOX/LOXL). This review examines how LOX/LOXLs were found to be dysregulated in noncancerous and cancerous settings, discusses their roles in solid tumor fibrosis and pathogenesis and explores the role of fibrosis in the development and poor clinical outcomes of patients with MPM. We examine the current preclinical status of drugs targeting LOX/LOXLs and how the incorporation of such drugs may have therapeutic benefits in the treatment and management of patients with MPM.

In plain English

This article was a review of lysyl oxidases (LOX and the LOX-like enzymes LOXL1 to LOXL4), enzymes that cross-link collagen, and their possible role in fibrosis in malignant pleural mesothelioma (MPM). The authors reviewed published work linking these enzymes to non-cancerous fibrotic diseases, to several solid cancers and to MPM, and reviewed drugs that block them. They also reported their own analyses. Using public gene-expression datasets, they found significantly altered LOX, LOXL1 and LOXL2 mRNA in MPM tissue compared with normal lung or pleura. In the TCGA mesothelioma dataset, higher combined expression of the five enzymes was associated with significantly worse overall survival. In plasma samples from 80 people with MPM and 40 benign samples, LOX activity was significantly higher in the MPM plasmas (p = 0.0002). Among the trials reviewed, the antibody simtuzumab was well tolerated but did not show efficacy. The authors concluded that lysyl oxidases play important roles in MPM and that targeting them has potential therapeutic implications. They noted that significant preclinical studies will be required to test combination treatments.

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 lysyl oxidases in fibrosis, cancer and MPM and of lysyl oxidase inhibitors, with the authors' own analyses of public gene-expression datasets and of LOX activity in patient plasma
• Who was studied: For the authors' own analyses: public MPM microarray data (Gordon et al. dataset via Oncomine), the TCGA mesothelioma dataset via Gepia2, and 120 plasma samples (40 benign, 80 malignant). The article does not say where or when the plasma samples were collected.
• Exposure: No asbestos exposure was studied or measured. The article concerns the expression and activity of the lysyl oxidase enzymes. Asbestos is mentioned only as background, as the cause of the inflammation that leads to mesothelioma.
• Main results:
  • In MPM tissues compared with normal lung or pleura (Gordon et al. dataset), mRNA expression was significantly altered for LOX (p = 3.9 × 10 to the minus 5), LOXL1 (p = 0.002) and LOXL2 (p = 5.3 × 10 to the minus 4).
  • In the TCGA mesothelioma dataset, the combined expression of LOX, LOXL1, LOXL2, LOXL3 and LOXL4 was split at the median. The high-expression group had significantly worse overall survival (p = 3.6 × 10 to the minus 6).
  • LOX activity, measured with a LOX-specific bioprobe assay, was significantly higher in plasma from the 80 MPM patients than in the 40 benign samples (p = 0.0002).
  • In the clinical trials reviewed, the LOXL2 antibody simtuzumab was well tolerated but did not show efficacy in cancers or fibrotic diseases.
• The authors' conclusion: The authors believed that lysyl oxidases play important roles in the development of mesothelioma and concluded that targeting them has potential therapeutic implications for its management.
• Limitations the authors state:
  • The authors stated that significant preclinical studies will be required to test combinations of lysyl oxidase inhibitors with checkpoint inhibitors or chemotherapy in mesothelioma.
  • The authors listed unanswered questions, including whether tumors will adapt to lysyl oxidase inhibition.

Topics

Medical terms in this study, explained in our Lexicon: Fibrosis, Mesothelioma, checkpoint inhibitors, Cisplatin, Pleural Mesothelioma, Collagen, Quality of Life.

Related studies

• Insights into the molecular mechanisms underlying the function of lysyl oxidase like 1 in cancers — X. Wang, X. Wang, et al. (2025)
• Inhibition of NADPH oxidase 4 induces apoptosis in malignant mesothelioma: Role of reactive oxygen species — M. Tanaka, Y. Miura, et al. (2015)
• A synergistic interaction between Bacillus Calmette-Guérin (BCG) and NADPH oxidase stimulants on the production of reactive oxygen metabolites by human mononuclear phagocytes — P.W. Nyberg, S.A. Nordman, et al. (1994)
• Asbestos exposure: a potential cause of retroperitoneal fibrosis — R. Sauni, P. Oksa, et al. (1998)
• KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma — S. Cregan, L. McDonagh, et al. (2016)
• In Silico and In Vitro Analyses of LncRNAs as Potential Regulators in the Transition from the Epithelioid to Sarcomatoid Histotype of Malignant Pleural Mesothelioma (MPM) — A.S. Singh, R. Heery, et al. (2018)

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