Molecular expression of glycosaminoglycans modifies the plasticity of biphasic mesothelioma in favor of tumor progression

Our plain-English summary of Molecular expression of glycosaminoglycans modifies the plasticity of biphasic mesothelioma in favor of tumor progression, by C.M. Baldavira, A.N. Qualiotto, T.G. Prieto, et al (Glycoconjugate Journal, 2025).

The study

• Authors: C.M. Baldavira, A.N. Qualiotto, T.G. Prieto, S. de Morais Fernezlian, A. Assato, M. Balancin, T. Takagaki, A. Ab'Saber, A.P.P. Velosa, W.R. Teodoro, V.L. Capelozzi
• Journal: Glycoconjugate Journal
• Published: 2025;42(5-6):295-306
• Read it: PubMed · Publisher · Free full text

Abstract

The study aimed to verify whether the expression of glycosaminoglycans (GAGs) and proteoglycans (PGs) in the tumor matrix affects the plasticity of mesothelioma and its relationship with the phenotype, progression, and resistance to treatment of malignant mesothelioma (MM). As MM is highly aggressive, understanding the molecular mechanisms that regulate the abilities of tumor cells to alter their behaviors and shapes is essential to the development of new therapeutic strategies. To test this hypothesis, we studied 66 samples of human biphasic MM. The expression levels of the GAGs heparan sulfate (HS) and chondroitin sulfate (SC), as well as the PGs versican, biglycan, and perlecan were detected using immunohistochemistry, and their expression was quantified using semi-automated digital analysis. We found that the fusiform phenotype of MM cells was associated with higher expression levels of HS, versican, and biglycan (all P-values < 0.001) in the extracellular matrix. This suggests that the increase and eventual rapid turnover of cell membrane PGs resulted in a variation in shape from polygonal to fusiform phenotypes, whereas GAGs were associated with cell aggregation-thus indicating the distinct functions of different GAGs. Multivariate Cox regression analysis showed that non-surgical patients (hazard ratio [HR]: 4.03 (1.26-12.82); P = 0.02), whose tumors presented necrosis (P < 0.001), high HS expression (P = 0.02), and low biglycan expression (HR: 2.68 [1.16-6.18]; P = 0.02) had significantly worse overall survival rates. We concluded that the expression of GAGs and PGs in the ECM affects the plasticity of MM, modifies its phenotype, and facilitates both its progression and resistance to treatment.

© 2025. The Author(s).

In plain English

This laboratory study from São Paulo, Brazil, examined tumor tissue from 66 patients with malignant pleural mesothelioma: 52 epithelioid and 14 biphasic tumors. The abstract describes all 66 as biphasic, but the article's results do not. The authors stained tumor samples for matrix molecules (heparan sulfate, chondroitin sulfate) and related proteins (versican, biglycan, perlecan), and measured them with image-analysis software. Thirty-six patients (54.5%) had been exposed to asbestos; fiber types were not reported. Biphasic tumors had higher median heparan sulfate than epithelioid tumors (25.75% vs 3.68%), as well as higher versican and biglycan. Higher heparan sulfate and versican were associated with asbestos exposure and older age. No single marker predicted survival alone, and asbestos exposure was not significantly linked to survival. In a combined analysis, worse survival was associated with not having surgery (hazard ratio 4.03, 1.26 to 12.82), tumor necrosis, high heparan sulfate and low biglycan (hazard ratio 2.68, 1.16 to 6.18). The authors concluded that these molecules modify tumor plasticity in favor of progression. They noted that immunohistochemistry limits precise measurement and that mechanistic studies 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: Laboratory (immunohistochemistry and immunofluorescence) study of tumor tissue samples from patients, with survival analysis using Kaplan–Meier and Cox regression
• Who was studied: 66 patients with malignant pleural mesothelioma from three University of São Paulo institutions in Brazil: 52 epithelioid and 14 biphasic tumors; 48 male; mean age 60 years; 38 died of mesothelioma-related complications during follow-up
• Exposure: History of asbestos exposure was recorded for each patient: 36 (54.5%) exposed and 30 (45.5%) not exposed. No fiber types, jobs or doses were given. The main measurements were tissue levels of heparan sulfate, chondroitin sulfate, versican, biglycan and perlecan.
• Main results:
  • Median heparan sulfate expression was 3.68% in epithelioid tumors vs 25.75% in biphasic tumors (P less than 0.001). Versican was 0.60% vs 12.83% (P less than 0.001).
  • Heparan sulfate, versican and biglycan were expressed mainly in the spindle-cell (fusocellular) components
  • Heparan sulfate expression was higher in tumors from older patients (P = 0.02) and from asbestos-exposed patients (P = 0.01)
  • High versican expression was also associated with older age and asbestos exposure (P = 0.03)
  • In unadjusted Cox analysis, asbestos exposure was not significantly associated with risk of death: HR 0.69 (0.33–1.46), P = 0.34, for not exposed vs exposed
  • In Kaplan–Meier analysis, no individual marker showed an independent effect on overall survival
  • In multivariate Cox analysis, lower overall survival was associated with: patients who did not undergo surgery (HR 4.03 [1.26–12.82]; P = 0.02); tumors with necrosis (P less than 0.001); high heparan sulfate expression (P = 0.02); and low biglycan expression (HR 2.68 [1.16–6.18]; P = 0.02)
• The authors' conclusion: The authors concluded that expression of glycosaminoglycans modifies the plasticity of biphasic malignant pleural mesothelioma, favoring tumor progression. They suggested the proteoglycan profile may be a risk biomarker for disease activity and prognosis.
• Limitations the authors state:
  • The analysis relied mainly on immunohistochemistry, which makes precise measurement of total chondroitin sulfate and heparan sulfate difficult because these molecules vary in structure
  • Mechanistic studies are needed to understand how the matrix components contribute to tumor progression

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: Biphasic Mesothelioma, Mesothelioma, Immunohistochemistry, P-Value, Hazard Ratio, Necrosis, Overall Survival.

Related studies

• The recovery and characterization of acid glycosaminoglycans in normal human urine. Influence of a circadian rhythm — J.E. Scott, D.J. Newton (1975)
• Effect of insulin and epidermal growth factors on the synthesis of glycosaminoglycans/proteoglycans in cultured human malignant mesothelioma cells of different phenotypic morphology — G.N. Tzanakakis, N.K. Karamanos, et al. (1996)
• The diagnostic utility of glycosaminoglycans (GAGs) in the early detection of cancer: a systematic review — S. Douglah, R. Khalil, et al. (2024)
• Glycosaminoglycans from two human malignant mesothelioma cell lines: determination, distribution, and effect of platelet-derived growth factor on their synthesis — G.N. Tzanakakis, N.K. Karamanos, et al. (1995)
• Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma — A.N. Qualiotto, C.M. Baldavira, et al. (2023)
• Molecular Mechanisms of Tumor Progression and Novel Therapeutic and Diagnostic Strategies in Mesothelioma — T. Kato, I. Tanaka, et al. (2025)

Browse return to medical research.