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Brain cancer is a malignancy with diverse origins. These may include cells that normally reside within the central nervous system (CNS) such as astrocytes, oligodendrocytes, neurons, ependymal cells and cells of the meninges, which upon transformation give rise to astrocytoma, oligodendroglioma, neuroblastoma, ependymoma and meningioma, respectively. Brain cancer is categorically unique from cancer that resides outside of the CNS, since it is segregated from normal immunosurveillance by the blood-brain barrier (BBB). Brain tumors are further distinguished from non-CNS tumors by residing in an anatomical compartment that lacks a normal lymphatic drainage system. Moreover, brain cancer includes those tumors that localize within the CNS, but have an initial origin from somewhere outside of the brain (i.e., metastases).
Mutations in the Tp53 tumor suppressor gene were first implicated in gliomagenesis almost 20 years ago owing to the increased development of gliomas (most commonly astrocytomas) in patients with the rare cancer‑predisposing disorder Li-Fraumeni syndrome, which is caused by mutations in Tp53. Subsequent investigations found Tp53 mutations to be a frequent characteristic of sporadic low‑grade astrocytic tumors and secondary glioblastomas. By contrast, primary glioblastomas were initially associated with genomic amplification and activating mutations in the epidermal growth factor receptor (EGFR) locus, the most frequent of these being the variant III deletion (vIII) that was found in 20–30% of all primary glioblastomas and 50–60% of those also exhibiting EGFR amplification.
In more recent years, additional cancer‑related genes and signaling networks have been directly implicated in glioma pathogenesis. The retinoblastoma (Rb) tumor suppressor pathway is defective in a significant number of high‑grade gliomas of both astrocytic and oligodendroglial lineage, whether by inactivating mutations in RB1 itself or amplification of its negative regulators cyclin‑dependent kinase 4 (CDK4) and, less frequently, CDK6. Analogously, amplification of the p53 antagonists MDM2 and MDM4 have also been found in distinct subsets of Tp53‑intact glioblastomas, as have mutations and/or deletions in the CDKN2A locus that encodes both INK4A and ARF, which are crucial positive regulators of RB and p53, respectively. Moreover, recent genome‑wide association screens have identified single nucleotide polymorphisms (SNPs) in the CDKN2A and adjacent CDKN2B loci as risk factors for glioma development. These studies have also associated SNPs in other genes, such as regulator of telomere elongation helicase 1 (RTEL1) and telomerase reverse transcriptase (TERT) with increased glioma incidence, providing the research community with a new set of molecular targets for investigation.
As our understanding of the intricacies of glioma and medulloblastoma biology has progressed, so too has the hope that such breakthroughs will lead to more effective, less toxic, rationally conceived therapeutics. Since the functional determinants driving brain tumorigenesis continue to be elucidated, revealing among other things the remarkable cellular and molecular heterogeneity, the opportunities for more targeted, individualized intervention seem to be increasing rapidly. Creative Biogene, as a leading biotechnology company, can offer various brain cancer pathway-related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.