Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland.
Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona.
Neuro Oncol. 2018 Sep 3;20(10):1321-1330. doi: 10.1093/neuonc/noy063.
Glioblastoma (GBM) is a difficult to treat brain cancer that nearly uniformly recurs, and recurrent tumors are largely therapy resistant. Our prior work has demonstrated an important role for the tumor necrosis factor-like weak inducer of apoptosis (TWEAK) receptor fibroblast growth factor-inducible 14 (Fn14) in GBM pathobiology. In this study, we investigated Fn14 expression in recurrent GBM and in the setting of temozolomide (TMZ) resistance.
Fn14 mRNA expression levels in nonneoplastic brain, primary (newly diagnosed) GBM, and recurrent GBM (post-chemotherapy and radiation) specimens were obtained from The Cancer Genome Atlas data portal. Immunohistochemistry was performed using nonneoplastic brain, patient-matched primary and recurrent GBM, and gliosarcoma (GSM) specimens to examine Fn14 protein levels. Western blot analysis was used to compare Fn14 expression in parental TMZ-sensitive or matched TMZ-resistant patient-derived xenografts (PDXs) established from primary or recurrent tumor samples. The migratory capacity of control and Fn14-depleted TMZ-resistant GBM cells was assessed using the transwell migration assay.
We found that Fn14 is more highly expressed in recurrent GBM tumors than their matched primary GBM counterparts. Fn14 expression is also significantly elevated in GSM tumors. GBM PDX cells with acquired TMZ resistance have higher Fn14 levels and greater migratory capacity than their corresponding parental TMZ-sensitive cells, and the migratory difference is due, at least in part, to Fn14 expression in the TMZ-resistant cells.
This study demonstrates that the Fn14 gene is highly expressed in recurrent GBM, GSM, and TMZ-resistant GBM PDX tumors. These findings suggest that Fn14 may be a valuable therapeutic target or drug delivery portal for treatment of recurrent GBM and GSM patients.
胶质母细胞瘤（GBM）是一种难以治疗的脑癌，几乎普遍复发，而复发性肿瘤在很大程度上对治疗具有抗性。我们之前的工作已经证明肿瘤坏死因子样凋亡弱诱导物（TWEAK）受体成纤维细胞生长因子诱导 14（Fn14）在 GBM 病理生物学中的重要作用。在这项研究中，我们研究了 Fn14 在复发性 GBM 中的表达以及在替莫唑胺（TMZ）耐药的情况下的表达。
从癌症基因组图谱数据门户获得非肿瘤性脑、原发性（新诊断）GBM 和复发性 GBM（化疗和放疗后）标本中的 Fn14 mRNA 表达水平。使用非肿瘤性脑、患者匹配的原发性和复发性 GBM 以及神经胶质瘤肉瘤（GSM）标本进行免疫组织化学检测，以检查 Fn14 蛋白水平。使用 Western blot 分析比较从原发性或复发性肿瘤样本建立的亲本 TMZ 敏感或匹配 TMZ 耐药患者来源异种移植（PDX）中 Fn14 的表达。使用 Transwell 迁移测定评估对照和 Fn14 耗竭的 TMZ 耐药 GBM 细胞的迁移能力。
我们发现 Fn14 在复发性 GBM 肿瘤中的表达高于其匹配的原发性 GBM 肿瘤。Fn14 的表达在 GSM 肿瘤中也显著升高。与相应的亲本 TMZ 敏感细胞相比，获得 TMZ 耐药的 GBM PDX 细胞具有更高的 Fn14 水平和更大的迁移能力，而这种迁移差异至少部分归因于 TMZ 耐药细胞中的 Fn14 表达。
这项研究表明，Fn14 基因在复发性 GBM、GSM 和 TMZ 耐药 GBM PDX 肿瘤中高度表达。这些发现表明，Fn14 可能是治疗复发性 GBM 和 GSM 患者的有价值的治疗靶点或药物输送门户。
