Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Glia. 2021 Sep;69(9):2199-2214. doi: 10.1002/glia.24018. Epub 2021 May 15.
High-grade gliomas (HGGs) are aggressive, treatment-resistant, and often fatal human brain cancers. The TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) signaling axis is involved in tissue repair after injury and constitutive signaling has been implicated in the pathogenesis of numerous solid cancers. The Fn14 gene is expressed at low levels in the normal, uninjured brain but is highly expressed in primary isocitrate dehydrogenase wild-type and recurrent HGGs. Fn14 signaling is implicated in numerous aspects of glioma biology including brain invasion and chemotherapy resistance, but whether Fn14 overexpression can directly promote tumor malignancy has not been reported. Here, we used the replication-competent avian sarcoma-leukosis virus/tumor virus A system to examine the impact of Fn14 expression on glioma development and pathobiology. We found that the sole addition of Fn14 to an established oncogenic cocktail previously shown to generate proneural-like gliomas led to the development of highly invasive and lethal brain cancer with striking biological features including extensive pseudopalisading necrosis, constitutive canonical and noncanonical NF-κB pathway signaling, and high plasminogen activator inhibitor-1 (PAI-1) expression. Analyses of HGG patient datasets revealed that high human PAI-1 gene (SERPINE1) expression correlates with shorter patient survival, and that the SERPINE1 and Fn14 (TNFRSF12A) genes are frequently co-expressed in bulk tumor tissues, in tumor subregions, and in malignant cells residing in the tumor microenvironment. These findings provide new insights into the potential importance of Fn14 in human HGG pathobiology and designate both the NF-κB signaling node and PAI-1 as potential targets for therapeutic intervention. MAIN POINTS: This work demonstrates that elevated levels of the TWEAK receptor Fn14 in tumor-initiating, neural progenitor cells leads to the transformation of proneural-like gliomas into more aggressive and lethal tumors that exhibit constitutive NF-κB pathway activation and plasminogen activator inhibitor-1 overexpression.
高级别神经胶质瘤（HGGs）是侵袭性的、治疗耐药的、且常导致死亡的人类脑癌。TNF 样凋亡弱诱导物（TWEAK）/成纤维细胞生长因子诱导 14（Fn14）信号轴参与损伤后的组织修复，而组成性信号已被牵连到许多实体癌的发病机制中。Fn14 基因在正常、未受损的大脑中低水平表达，但在原发性异柠檬酸脱氢酶野生型和复发性 HGGs 中高度表达。Fn14 信号参与神经胶质瘤生物学的许多方面，包括脑侵袭和化疗耐药，但 Fn14 过表达是否能直接促进肿瘤恶性尚未有报道。在这里，我们使用复制型禽肉瘤白血病病毒/肿瘤病毒 A 系统来研究 Fn14 表达对神经胶质瘤发生和病理生物学的影响。我们发现，仅将 Fn14 添加到先前显示可产生类神经前体细胞神经胶质瘤的致癌鸡尾酒中，就会导致具有显著生物学特征的高度侵袭性和致命性脑癌的发展，包括广泛的假栅状坏死、组成性经典和非经典 NF-κB 途径信号和高水平的纤溶酶原激活物抑制剂-1（PAI-1）表达。对 HGG 患者数据集的分析表明，高人类 PAI-1 基因（SERPINE1）表达与患者生存时间缩短相关，并且 SERPINE1 和 Fn14（TNFRSF12A）基因在肿瘤组织、肿瘤亚区和肿瘤微环境中恶性细胞中经常共同表达。这些发现为 Fn14 在人类 HGG 病理生物学中的潜在重要性提供了新的见解，并将 NF-κB 信号节点和 PAI-1 指定为治疗干预的潜在靶点。主要观点：本研究表明，在肿瘤起始的神经祖细胞中，TWEAK 受体 Fn14 水平升高会导致类神经前体细胞神经胶质瘤向更具侵袭性和致命性的肿瘤转化，这些肿瘤表现出组成性 NF-κB 途径激活和纤溶酶原激活物抑制剂-1 过表达。
