| Vascular endothelial growth factor (VEGF) and VEGFRs directed monoclonal antibodies 75,76
|
• Upregulation of VEGF and its receptors VEGFR-1 and VEGFR-2 activated by VEGF-A is often allied with cell proliferation, tumor invasion, migration and permeability
• Proliferating and migrating endothelial cells are regulated by VEGFR incited Ras/Raf/mitogen-activated protein kinase and phospholipase C-γ/protein kinase C signaling cascades
• VEGF ligand promotes tumor growth by both autocrine and paracrine manner |
| Platelet-derived growth factor (PDGF) 77,78
|
• Correlation exists between abnormal PDGF signalling and glioma
• Both autocrine and paracrine mechanisms involvement in gliomas (downregulation of PDGF-mediated signaling) |
| Epidermal Growth Factor Receptors (EGFRs) 76
|
• Involved in tumorigenesis, differentiation, migration, proliferation, neural cell survival, neural cell fate and astrocyte differentiation
• EGFRvIII, the most common mutation in gliomas enhancing tumorigenic behavior and causing genetic instability |
| PI3K and Akt pathway and PI3K/Akt 75,76,79,80
|
• During downstream of RTK signaling, Ras/Raf/MAPK and AKT/PI3K are activated. The PI3K-Akt is generally up-regulated in malignant gliomas and GBM
• Akt's up-regulation enable glioma cells to grow continuously, evade apoptosis, and augment tumor invasion
• PI3K dependent activation of Akt is inhibited by PTEN, AKT/PI3K is constitutively activated by mutation or loss of PTEN
• Combination of activated Akt and constitutively active EGFR signaling induces glial tumor formation along with genetic instability |
| Mammalian target of rapamycin (mTOR) 81,82
|
• Cancer growth eventuates by mTOR activation of lipid and protein biosynthesis during which signal transduction gets deregulated and mTORC1 effectors (S6K1 and eIF4E) gets up-regulated
• TSC syndrome leads to upregulation in mTOR pathway and subsequent downstream kinase signalling cascade alters cell processes
• Increased mTOR activity with upregulation of p70S6K has been observed in both healthy and lesioned skin biopsies of TS patients. The secretory agents from endothelial cells of brain maintain GBM stem-like cell growth by mTOR pathway |
| Notch pathway 83,84,85
|
• Influences neural stem cell renewal, progenitor cell differentiation, learning, memory, and gliogenesis
• Notch1 and its ligands Delta-like 1 and Jagged1 are crucial for GBM cell growth |
| Matrix metalloproteinase (MMP) family 75
|
• MMP-2 & -9 manifests a significant role in extracellular matrix degradation, neoangiogenesis and tumor vascularisation |
