Glioblastoma Multiforme (GBM) is an aggressive neoplasm with an elevated, often aberrant, proliferative capacity and a diffuse pattern of brain invasion. It is the most malignant astrocytic tumor composed of poorly differentiated neoplastic astrocytes. GBM, also known as WHO grade-IV astrocytoma, is divided into two subtypes based on clinical characteristics: primary and secondary GBM. Primary GBM arises as a de novo process in the absence of a pre-existing low grade lesion, whereas secondary GBM develops progressively from a low grade astrocytoma, generally over a period of 5-10 years. Although most neurological tumors are of glial origin, it is unclear whether tumor cells result from the transformation of an immature precursor or from the de-differentiation 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.A high percentage (50%-60%) of GBMs display an overexpression/amplification of RTKs such as EGFR, PDGFR and IGF1R. Post ligand binding, RTKs undergo receptor dimerization, autophosphorylation and recruitment of adaptor proteins such as SHC, SOS and GRB2 that interact with and activate various downstream pathways including the Ras/Raf/ERK, PI3K/AKT and Cdc42-Rac-Rho pathways. Deregulation of these pathways ultimately leads to manifestation of GBM. For example, Ras signaling is negatively controlled by NF (Neurofibromins). NF1 catalyzes the conversion of activated Ras-GTP to inactive Ras-GDP thereby negatively regulating cellular Ras activity. Disruption of NF1 function causes Neurofibromatosis type-I, a familial cancer syndrome which involves the development of multiple benign and malignant tumors of the CNS and PNS. Elevated expression of PDGF/PDGFR occurs in every grade of astrocytoma. Furthermore, PDGF and PDGFR are often co-expressed in the same tumor cells indicating that astrocytoma cells establish an autocrine stimulatory loop. PKC-δ also plays an important role in GBM where it is activated downstream of the RTK signaling pathways. PKC-δ and c-Src are involved in the transactivation of EGFR during the development of glioblastomas. The non-receptor tyrosine kinase, c-Src, phosphorylates EGFR, leading to an increase in EGFR kinase activity. The existence of cross-talk between PKC-δ and EGFR provides a useful therapeutic target. Gene silencing of PKC-δ and c-Src with siRNA and pharmacological inhibition with Rottlerin attenuate the process of EGFR/c-Src/PKC-δ induced cell proliferation in glioblastoma cells. The PI3K/AKT signaling pathway plays a role in the the development of GBM by its regulation of the TSC1-TSC2 complex that is linked to cell growth. AKT also regulates effects of transcriptional regulator FOXO1 and MDM2.
A hallmark of high grade astrocytomas is high mitotic activity due to a lack of regulation of the G1/S-phase checkpoint. Mutations in the p14(ARF) and Rb proteins are both linked to disruption of the G1/S phase transition. The WNT/Fzd signaling that presents during tumor suppression in the cerebellum also plays a vital role in controlling brain tumors. In the absence of WNT signaling, Ctnn-β is associated with a cytoplasmic complex containing CK1-α, GSK3-β, AXIN and APC, which targets CTNN-β to proteasomal degradation. Mutations in AXIN, Ctnn-β or germline mutations of APC predispose the glial cells towards development of GBMs. Under such conditions, Ctnn-β translocates to the nucleus and interacts with LEF1 and TCF3/4 to induce c-Myc and Cyclin D1 gene expression leading to cell proliferation and eventually GBM. Mutational analysis indicates that key signaling pathways are disrupted in primary as well as secondary GBM.