Pathogenesis of Gliomas
Tumors of the Central Nervous System (CNS) are devastating as they are difficult to treat and may cause grave disability or death. CNS Gliomas pose particularly difficult problems because of their tendency toward malignancy, rate of tumor spread, and the lack of effective therapy. Gliomas are the most common intracranial malignant tumors in humans (Ref.1). In vertebrates, the embryonic neural tube (neuroectoderm) gives rise to the main cell types of the CNS, including neurons, astrocytes, oligodendrocytes and ependymal cells. The neural crest derives from the dorsal lip of the neural tube, and its cells migrate extensively during embryonic development, giving rise to various tissues, including the Peripheral Nervous System (PNS). In both the CNS and PNS, the appearance of neurons (Neurogenesis) developmentally precedes the appearance of glia (Gliogenesis). Neuroectodermal tumors (neurological tumors) include all neoplasms that have either a CNS or PNS derived cell of origin. The classification of neurological tumors is based on the predominant cell type(s), which is generally determined by morphological and immuno-histochemical criteria. After development ceases, neurons become post-mitotic and only a small compartment of stem cells remain, whereas glial cells retain the ability to proliferate throughout life. In this context, it is perhaps not surprising that most adult neurological tumors are of glial origin. These tumors are termed Gliomas, and include tumors that are composed predominantly of astrocytes (Astrocytomas), oligodendrocytes (Oligodendrogliomas), ependymal cells (Ependymomas) and mixtures of various glial cells (for example, Oligoastrocytomas or Glioblastoma with Oligodendroglial Component (GBMO)). In the case of the PNS, the Neurofibroma and Schwannoma are the two most common glial tumors. Of all the various grading schemes, the World Health Organization (WHO) grading system is most widely used. The WHO grading system classifies Gliomas into Grades I-IV based on the degree of malignancy, as determined by histopathological criteria. In the CNS, Grade-I Gliomas generally behave in a benign fashion and might even be circumscribed, whereas Grade-II, Grade-III and Grade-IV Gliomas are malignant and diffusely infiltrate throughout the brain. Astrocytomas are the most common CNS neoplasms, accounting for more than sixty percent of all primary brain tumors. Among Astrocytic Gliomas, Glioblastoma Multiforme (GBM) or WHO Grade-IV Astrocytoma, is the most common and aggressive type. Glioblastoma Multiforme poses a unique challenge because of its propensity for invasion and proliferation. Astrocytomas infiltrate throughout the brain and unfortunately, these tumors are largely resistant to radiation and chemotherapy (Ref.1 & 2).
WHO Grade-IV Astrocytoma are divided into two subtypes based on clinical characteristics: Primary and Secondary GBM. Primary GBM/Primary Glioblastoma Multiforme arises as a de novo process, in the absence of a pre-existing low-grade lesion, whereas Secondary GBM/Secondary Glioblastoma Multiforme develops progressively from Low-Grade Astrocytoma, generally over a period of 5-10 years. Under normal conditions immature precursor cells, otherwise known as glial progenitor cells differentiate into astrocytes, oligodendrocytes and ependymal cells. Although most neurological tumors are of glial-lineage origin, however it is unclear whether tumor cells result from the transformation of an immature precursor or from the dedifferentiation of a mature glial cell. Several genetic pathways are involved in the initiation and progression of these neoplasms, particularly during the manifestation of Secondary GBMs (Ref.3). They include two main early alterations: p53 inactivation (associated with Astrocytomas) and the loss of 1p and 19q chromosomes (more specific to Oligodendrogliomas), both mutually exclusive. Genetic pathways altered during initiation versus progression of Secondary GBMs includes the following: LOH (Loss of Heterozygosity) in chromosome 17p; over-expression ofPDGF/PDGFR (Platelet Derived Growth Factor/PDGF Receptor); p16(INK4A) (also known as p14(ARF) or CDKN2A), MDM2 (Mouse Double Minute-2) and GAC1 (Glioma Amplified on Chromosome-1) amplification; MGMT (Methylguanine-DNA Methyltransferase), TIMP3 (Tissue Inhibitor of Metalloproteinase-3) hypermethylation and loss of chromosome 22q, transforms normal astrocytes into Low-Grade Astrocytoma (WHO Grade-II), whereas, loss of NF1 (Neurofibromatosis Type-1) are involved in the initiation of Pilocytic Astrocytoma (WHO Grade-I). Pilocytic Astrocytoma is a brain tumor that occurs predominantly in children and involves the midline, basal and posterior fossa structures. It is generally considered a benign tumor of childhood. It is often cystic and if solid, it tends to be well circumscribed. Grade-I and Grade-II tumors further progress to Anaplastic Astrocytoma (WHO Grade-III) or Secondary GBM (WHO Grade-IV). Anaplastic Astrocytoma is associated with disruption of the Rb (Retinoblastoma) pathway (through loss of Rb or amplification/over-expression of CDK4 (Cyclin-Dependent Kinase-4)); LOH in chromosomes 9p, 10q, 11p and 19q; EGFR (Epidermal Growth Factor Receptor) amplification and loss of p16(INK4A)/p14(ARF) gene functions. Similarly, Rb hypermethylation; PDGFR-Alpha (Platelet-Derived Growth Factor Receptor-Alpha), MDM2, CDK4 gene amplification; and LOH in chromosome 10q are the chiefly associated with the manifestation of Secondary GBMs (Ref.4 & 5).
During Primary de novo GBM (WHO Grade-IV), the same genetic pathways are dismantled in developing astrocytes or glial progenitor cells, although through different mechanisms. Primary GBM often includes disruption of the p53 pathway through loss of the gene that encodes p14(ARF), or less frequently through amplification of MDM2. Disruption of the Rb pathway occurs through deletion of the gene that encodes p16(INK4A) Amplification and/or mutations of the gene that encodes EGFR are the most frequent genetic defect that is associated with Primary GBM. Activity of the phosphatase PTEN (Phosphatase and Tensin Homolog) is also frequently disrupted in this type of tumor along with other associated factors like MGMT, p16(INK4A)/p14(ARF) hypermethylations and LOH in 10p, 10q chromosomes. In Low-Grade Oligodendrogliomas (WHO Grade-II), the most characteristic genetic alterations are loss of chromosome 1p and 19q, tightly linked with one another. Both alterations appear early in tumorigenesis. Again loss of 9p chromosomes and loss of p16(INK4A)/p14(ARF) gene functions lead to the manifestation of Anaplastic Oligodendroglioma (WHO Grade-III). Further, EGFR over-expression or PTEN inactivation or loss of chromosome 10 contributes towards Glioma dissemination and development of GBMO (Glioblastoma with Oligodendroglial Component), (WHO Grade-IV) (Ref.2 & 3). Apart from Astrocytic tumors, Oligodendroglial tumors and mixed Gliomas, Gliomas of neuroepithelial origin also include and Ependymomas. Loss of chromosome 22q and mutations in NF2 (Neurofibromatosis Type-2) gene function in wild type ependymal cells are the major cause of Ependymomas which in the long term undergo metastasis and develop into mixed Gliomas or Secondary GBMs. The genetic mechanisms of such Glioma carcinogenesis include turning on oncogenes and inactivation of tumors suppressors. Although tools of molecular biology are very effective in deciphering the enigmas of cancer but currently, the major obstacle presents the selective delivery of genes to the neoplastic cells in vivo, especially in highly infiltrating tumors such as Glioblastoma Multiforme. Emerging techniques like comparative genomic hybridization array, gene profiling by microarray, and proteome analysis provide powerful approaches to identify new critical genes and to define a molecular classification based on homogenous clusters of tumors. However, despite the fact that the molecular changes underlying the tumor phenotype are understood better, treatment of Gliomas remains a huge challenge. There is a reasonable hope that targeted therapies that have already proven their efficacy in other cancers may also be successful for Gliomas in the future. As malignant Gliomas contain numerous molecular alterations, such therapies may probably be used in synergistic association with either conventional treatment or other biologic therapies targeted to different critical molecular pathways which are genetically altered during Gliomas (Ref.6 & 7).