Abstract
Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central nervous system (CNS) microenvironment. This review summarizes the salient contributions of oxidative stress, interleukins, tumor necrosis factor-α(TNF-α), cyclooxygenases, and transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and the associated cross-talks to the inflammatory signaling in CNS cancers. The roles of reactive astrocytes, tumor associated microglia and macrophages, metabolic alterations, microsatellite instability, O6-methylguanine DNA methyltransferase (MGMT) DNA repair and epigenetic alterations mediated by the isocitrate dehydrogenase 1 (IDH1) mutations have been discussed. The inflammatory pathways with relevance to the brain cancer treatments have been highlighted.
Highlights
Primary brain tumors are most common malignancies (85–90%) of the central nervous system (CNS) [1]
The glioblastoma multiforme (GBM), a grade IV tumor accounts for 80% of all primary brain cancers
Tumor Necrosis Factor-α (TNF-α) is responsible for dendritic cell (DC) maturation whereas, in tumorigenic conditions its expression correlates with GBM tumor grade [63]. 80% of anaplastic GBM tumors and 17% of astrocytoma and oligoastrocytoma express TNF-α [64]
Summary
Primary brain tumors are most common malignancies (85–90%) of the central nervous system (CNS) [1]. Alterations of four major pathways have been found in brain cancers, where at least one member of the signaling or metabolic circuit is mutated: RTK (receptor tyrosine kinases)/RAS (rat sarcoma)/PI3K (phosphotidylinositol-3-kinase) pathway, p53 pathway, RB pathway and the isocitrate dehydrogenase 1 or 2 (IDH1/2) pathway [7,8] All these alterations confer carcinogenic characteristics in cells by several key changes that include promotion of growth signals, non-responsiveness to antigrowth signals, evasion from apoptosis and acquisition of metastatic potential. The brain tumor is A2 composed different types Ʌ ofsurvival cells,\textturnedcapitalv including infiltrative deprivation and cells maintains neuronal connectivity, the A1 reactive astrocytes appear neurotoxicmarkers in inflammatory cells, with stem-like properties, and cells with and myeloid.
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