Department of Cell, Developmental, and Integrative Biology, University of Birmingham at Alabama, Birmingham, AL 35233, USA.
Research Department, Imperial College London Diabetes Centre, Abu Dhabi P.O. Box 48338, UAE.
Biomolecules. 2020 Sep 23;10(10):1357. doi: 10.3390/biom10101357.
Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood-brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.
胶质母细胞瘤（GBM）是一种原发性恶性脑肿瘤，预后较差，部分原因是我们无法完全切除和杀死所有 GBM 细胞。由于目前的标准治疗方法包括最大限度的手术切除、放疗和替莫唑胺（TMZ），一种血脑屏障（BBB）穿透化疗，肿瘤快速复发导致中位生存期仅为 15 个月。放疗和 TMZ 导致神经鞘磷脂酶（SMase）水解神经鞘磷脂生成神经酰胺，诱导细胞凋亡。然而，细胞可以通过将神经酰胺转化为鞘氨醇-1-磷酸（S1P）来逃避凋亡。S1P 与包括 GBM 在内的多种癌症有关。S1P 的上调与 GBM 和其他具有脑转移倾向的癌症的增殖和侵袭有关。为了介导其生物学效应，SMases 和 S1P 通过磷脂酶 C（PLC）和磷脂酶 D（PLD）调节信号。此外，SMase 和 S1P 都可能改变 BBB 的完整性，导致促进肿瘤的免疫细胞浸润。SMase 活性与肿瘤逃避免疫系统有关，而 S1P 为先天和适应性免疫细胞的运输创造了梯度。这篇综述将探讨鞘脂代谢和药物干预在 GBM 和转移性脑肿瘤中的作用，重点关注 SMase 和 S1P。
Zotero 插件
