Alghamri Mahmoud S, McClellan Brandon L, Hartlage Carson S, Haase Santiago, Faisal Syed Mohd, Thalla Rohit, Dabaja Ali, Banerjee Kaushik, Carney Stephen V, Mujeeb Anzar A, Olin Michael R, Moon James J, Schwendeman Anna, Lowenstein Pedro R, Castro Maria G
Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, United States.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States.
Front Pharmacol. 2021 May 18;12:680021. doi: 10.3389/fphar.2021.680021. eCollection 2021.
Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as loss, and mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system's response to cancer can impact the glioma's survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.
神经胶质瘤是最致命的癌症类型之一，约占所有中枢神经系统（CNS）原发性恶性肿瘤的80%。在神经胶质瘤中，胶质母细胞瘤（GBM）最为侵袭性，患者中位生存期少于15个月。最近的分子特征研究揭示了神经胶质瘤的基因特征和甲基化状态，并将这些与临床预后相关联。新的神经胶质瘤分类中最相关的分子特征是突变、1号染色体短臂/19号染色体长臂缺失、组蛋白突变以及其他遗传参数，如缺失、突变以及DNA甲基化水平。与其他实体瘤类似，神经胶质瘤的进展受到肿瘤微环境中肿瘤细胞与免疫细胞之间复杂相互作用的影响。免疫系统对癌症的反应会影响神经胶质瘤的存活、增殖和侵袭性。神经胶质瘤的显著特征包括血管生成增强、低氧肿瘤微环境的刺激、氧化应激增加以及免疫抑制环境。这些过程促进了神经炎症性肿瘤微环境，可导致血脑屏障（BBB）完整性丧失。血脑屏障受损的后果是有害地使大脑暴露于外周循环中潜在有害浓度的物质，对神经元信号传导产生不利影响，并导致异常免疫细胞浸润；所有这些都可导致脑稳态破坏。在本综述中，我们首先描述中枢神经系统肿瘤中炎症的独特特征。然后我们讨论肿瘤起始神经炎症微环境的机制及其对肿瘤侵袭和进展的影响。最后，我们还讨论可用于靶向神经胶质瘤中神经炎症的潜在药物干预措施。
