Wei Ruolun, Xie Haoyun, Zhou Yukun, Chen Xuhao, Zhang Liwei, Bui Brandon, Liu Xianzhi
Department of Neurosurgery, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China.
Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA, United States.
Front Neurosci. 2024 Nov 1;18:1501906. doi: 10.3389/fnins.2024.1501906. eCollection 2024.
Gliomas are the most prevalent primary malignant intracranial tumors, characterized by high rates of therapy resistance, recurrence, and mortality. A major factor contributing to the poor prognosis of gliomas is their ability to diffusely infiltrate surrounding and even distant brain tissues, rendering complete total resection almost impossible and leading to frequent recurrences. The extracellular matrix (ECM) plays a key role in the tumor microenvironment and may significantly influence glioma progression, recurrence, and therapeutic response.
In this study, we first identified the ECM and the Versican (VCAN), a key ECM protein, as critical contributors to glioma recurrence through a comprehensive analysis of transcriptomic data comparing recurrent and primary gliomas. Using single-cell sequencing, we revealed heterogeneous distribution patterns and extensive intercellular communication among ECM components. External sequencing and immunohistochemical (IHC) staining further validated that VCAN is significantly upregulated in recurrent gliomas and is associated with poor patient outcomes.
Functional assays conducted in glioma cell lines overexpressing VCAN demonstrated that VCAN promotes cell proliferation and migration via the PI3K/Akt/AP-1 signaling pathway. Furthermore, inhibiting the PI3K/Akt pathway effectively blocked VCAN-mediated glioma progression.
These findings provide valuable insights into the mechanisms underlying glioma recurrence and suggest that targeting both VCAN and the PI3K/Akt pathway could represent a promising therapeutic strategy for managing recurrent gliomas.
胶质瘤是最常见的原发性恶性颅内肿瘤，其特征是治疗耐药、复发和死亡率高。胶质瘤预后不良的一个主要因素是它们能够弥漫性浸润周围甚至远处的脑组织，使得几乎不可能进行完全切除，并导致频繁复发。细胞外基质（ECM）在肿瘤微环境中起关键作用，可能会显著影响胶质瘤的进展、复发和治疗反应。
在本研究中，我们首先通过对比较复发性和原发性胶质瘤的转录组数据进行全面分析，确定细胞外基质和关键的细胞外基质蛋白多功能蛋白聚糖（VCAN）是胶质瘤复发的关键因素。使用单细胞测序，我们揭示了细胞外基质成分的异质分布模式和广泛的细胞间通讯。外部测序和免疫组织化学（IHC）染色进一步验证了VCAN在复发性胶质瘤中显著上调，并且与患者的不良预后相关。
在过表达VCAN的胶质瘤细胞系中进行的功能分析表明，VCAN通过PI3K/Akt/AP-1信号通路促进细胞增殖和迁移。此外，抑制PI3K/Akt通路有效地阻断了VCAN介导的胶质瘤进展。
这些发现为胶质瘤复发的潜在机制提供了有价值的见解，并表明靶向VCAN和PI3K/Akt通路可能是治疗复发性胶质瘤的一种有前景的治疗策略。
