Baldavira Camila Machado, Qualiotto Aline Nery, Prieto Tabatha Gutierrez, de Morais Fernezlian Sandra, Assato Aline, Balancin Marcelo, Takagaki Teresa, Ab'Saber Alexandre, Velosa Ana Paula Pereira, Teodoro Walcy Rosolia, Capelozzi Vera Luiza
Department of Pathology, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Division of Pneumology, Instituto do Coração (Incor), University of São Paulo Medical School (USP), São Paulo, Brazil.
Glycoconj J. 2025 Aug 13. doi: 10.1007/s10719-025-10192-z.
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.
该研究旨在验证肿瘤基质中糖胺聚糖（GAGs）和蛋白聚糖（PGs）的表达是否会影响间皮瘤的可塑性及其与恶性间皮瘤（MM）的表型、进展和治疗耐药性之间的关系。由于MM具有高度侵袭性，了解调节肿瘤细胞改变其行为和形状能力的分子机制对于开发新的治疗策略至关重要。为了验证这一假设，我们研究了66例人双相MM样本。使用免疫组织化学检测GAGs硫酸乙酰肝素（HS）和硫酸软骨素（SC）以及PGs多功能蛋白聚糖、双糖链蛋白聚糖和基底膜聚糖的表达水平，并使用半自动数字分析对其表达进行定量。我们发现MM细胞的梭形表型与细胞外基质中HS、多功能蛋白聚糖和双糖链蛋白聚糖的较高表达水平相关（所有P值均<0.001）。这表明细胞膜PGs的增加以及最终的快速周转导致细胞形状从多边形变为梭形，而GAGs与细胞聚集相关，从而表明不同GAGs具有不同的功能。多变量Cox回归分析显示，非手术患者（风险比[HR]：4.03[1.26 - 12.82]；P = 0.02），其肿瘤出现坏死（P < 0.001）、HS高表达（P = 0.02）和双糖链蛋白聚糖低表达（HR：2.68[1.16 - 6.18]；P = 0.02），其总生存率显著更差。我们得出结论，ECM中GAGs和PGs的表达会影响MM的可塑性，改变其表型，并促进其进展和治疗耐药性。
