Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

Abstract

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 IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT 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.

Neuroinflammation and immunoregulation in glioblastoma and brain metastases: Recent developments in imaging approaches

“…One common feature of GBM is tissue necrosis accompanied by microenvironment inflammation. Immunosuppressive inflammation with associated necrosis is typical of GBMs that display higher resistance to therapies and a worst prognosis [16][17][18][19][20]. GBM cells express and secrete immune suppressive chemokines and cytokines, including interleukin (IL)-6, IL-10, transforming growth factor (TGF)-β, galectin-1 and prostaglandin-E, which act on infiltrating immune cells to hijack them by inducing a protumor cellular phenotype.…”

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

“…Fourth, approximately 80% of MBT arises from glia cells [80] but secondary glioblastomas with genetic mutations in isocitrate dehydrogenase, TP53 or ATRX, etc. are rare [81].…”

Brain tumours, brain metastases, and neuroinflammation: Insights from neuroimaging studies.

“…One common feature of GBM is tissue necrosis accompanied by microenvironment inflammation. Immunosuppressive inflammation with associated necrosis is typical of GBMs that display higher resistance to therapies and worst prognosis [16][17][18][19][20]. GBM cells express and secrete immune suppressive chemokines and cytokines including interleukin-6, interleukin-10, transforming growth factor (TGF)-β, galectin-1, and prostaglandin-E, which act on infiltrating immune cells to hijack them by inducing a pro-tumor cellular phenotype.…”

“…These immunosuppressive changes enabled by inflammatory mediators stimulate GBM cell proliferation, migration, angiogenesis, and resistance to treatment. For example, signaling mediated by CXCR3 and CCR2 receptors recruit tumor-promoting immune cells such as T cells and myeloidderived suppressor cells [16,[21][22][23][24][25][26][27][28]. In GBM cancer stem cells (CSCs), hypoxic tissue triggers expression of genes of the inflammatory reparative response [25,29].…”