Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona.
Mol Cancer Res. 2018 Feb;16(2):322-332. doi: 10.1158/1541-7786.MCR-17-0454. Epub 2017 Nov 8.
Glioblastoma is the most frequent primary brain tumor in adults and a highly lethal malignancy with a median survival of about 15 months. The aggressive invasion of the surrounding normal brain makes complete surgical resection impossible, increases the resistance to radiation and chemotherapy, and assures tumor recurrence. Thus, there is an urgent need to develop innovative therapeutics to target the invasive tumor cells for improved treatment outcomes of this disease. Expression of TROY (TNFRSF19), a member of the tumor necrosis factor (TNF) receptor family, increases with increasing glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates glioblastoma cell invasion and and increases resistance to temozolomide and radiation therapy. Conversely, silencing TROY expression inhibits glioblastoma cell invasion, increases temozolomide sensitivity, and prolongs survival in an intracranial xenograft model. Here, a novel complex is identified between TROY and EGFR, which is mediated predominantly by the cysteine-rich CRD3 domain of TROY. Glioblastoma tumors with elevated TROY expression have a statistically positive correlation with increased EGFR expression. TROY expression significantly increases the capacity of EGF to stimulate glioblastoma cell invasion, whereas depletion of TROY expression blocks EGF stimulation of glioblastoma cell invasion. Mechanistically, TROY expression modulates EGFR signaling by facilitating EGFR activation and delaying EGFR receptor internalization. Moreover, the association of EGFR with TROY increases TROY-induced NF-κB activation. These findings substantiate a critical role for the TROY-EGFR complex in regulation of glioblastoma cell invasion. The TROY-EGFR signaling complex emerges as a potential therapeutic target to inhibit glioblastoma cell invasion. .
胶质母细胞瘤是成人中最常见的原发性脑肿瘤，是一种高度致命的恶性肿瘤，中位生存期约为 15 个月。其周围正常脑组织的侵袭性浸润使得完全手术切除成为不可能，增加了对放疗和化疗的抵抗，并确保肿瘤复发。因此，迫切需要开发创新的治疗方法来靶向侵袭性肿瘤细胞，以改善这种疾病的治疗效果。肿瘤坏死因子（TNF）受体家族成员 TROY（TNFRSF19）的表达随着神经胶质瘤肿瘤分级的增加而增加，并与患者的生存呈负相关。TROY 的表达增加刺激胶质母细胞瘤细胞侵袭，并增加对替莫唑胺和顺铂治疗的抵抗。相反，沉默 TROY 表达可抑制胶质母细胞瘤细胞侵袭，增加替莫唑胺敏感性，并延长颅内异种移植模型中的生存时间。在这里，鉴定到 TROY 和 EGFR 之间存在一种新的复合物，该复合物主要由 TROY 的富含半胱氨酸的 CRD3 结构域介导。TROY 表达升高的胶质母细胞瘤肿瘤与 EGFR 表达增加具有统计学上的正相关性。TROY 表达显著增加了 EGF 刺激胶质母细胞瘤细胞侵袭的能力，而 TROY 表达的耗竭则阻断了 EGF 刺激胶质母细胞瘤细胞侵袭的能力。从机制上讲，TROY 表达通过促进 EGFR 激活和延迟 EGFR 受体内化来调节 EGFR 信号。此外，EGFR 与 TROY 的结合增加了 TROY 诱导的 NF-κB 激活。这些发现证实了 TROY-EGFR 复合物在调节胶质母细胞瘤细胞侵袭中的关键作用。TROY-EGFR 信号复合物是抑制胶质母细胞瘤细胞侵袭的潜在治疗靶点。
