Aberrant signaling pathways in glioma

Abstract

Glioblastoma multiforme (GBM), a WHO grade IV malignant glioma, is the most common and lethal primary brain tumor in adults; few treatments are available. Median survival rates range from 12-15 months. The biological characteristics of this tumor are exemplified by prominent proliferation, active invasiveness, and rich angiogenesis. This is mainly due to highly deregulated signaling pathways in the tumor. Studies of these signaling pathways have greatly increased our understanding of the biology and clinical behavior of GBM. An integrated view of signal transduction will provide a more useful approach in designing novel therapies for this devastating disease. In this review, we summarize the current understanding of GBM signaling pathways with a focus on potential molecular targets for anti-signaling molecular therapies.

Figure 1.

Representative radiological findings of GBM. Gadolinium-enhanced T1-weighted MRI (A, axial section; C, coronal section; D, sagittal section) shows a ring enhancement lesion in the right temporo-parietal lobe with midline shift. T2-weighted (B) image showed prominent peritumoral edema.

Figure 2.

Major events during gliomagenesis. Neoplastic transformation in GBM is attributed to the progressive accumulation of multiple intracellular events.

Figure 3.

Main proliferation signaling pathways. The PI3K/Akt/mTOR and Ras/Raf/MAPK pathways are shown. Growth factors bind to Receptor tyrosine kinases (RTKs), followed by activation of Ras/Raf/MAPK and/or PI3K/Akt/mTOR. Raf, MAPK, Akt, and mTOR are classified as serine/threonine-specific protein kinases (STKs). Intracellular tyrosine kinase c-src also activates Ras/Raf/MAPK. Nuclear factor NF-κB also plays an important role in cell proliferation. Ras/Raf/MAPK and PI3K/Akt/mTOR signaling pathways are depicted in detail in Figures 6 and 8, respectively. Solid and dashed arrows indicate activation and suppression, respectively. c-src: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian); MAPK: Mitogen-activated protein (MAP) kinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NF-1: neurofibromin 1; NRTK: non-receptor tyrosine kinase; PI3K: phosphatidylinositol 3-kinases; PTEN: phosphatase and tensin homolog.

Figure 4.

A schematic diagram of angiogenesis in gliomas. Angiogenesis is initiated by angiogenic factors, which are released from glioma cells in the hypoxic glioma microenvironment. Major angiogenic factors include VEGF and FGF. Upon binding to their cognate receptors on endothelial cells, angiogenic factors trigger endothelial cell proliferation and migration. After degradation of ECM, endothelial cells are assembled into a tubular lumen. The final process is maturation of the vessel wall, which is constructed by recruitment of pericytes to assemble along the endothelial cells outside the new vessel.

Figure 5.

Novel signaling influences glioma invasion. The main signaling pathways involve PI3K/Akt and small GTPases (Rac1, cdc42, RhoA). Solid and dashed arrows indicate activation and suppression, respectively. FAK: focal adhesion kinase; Gi: inhibitory G-protein; GPCR: G-protein-coupled receptor; HA: hyaluronic acid; JNK: c-Jun terminal kinase; LPA: lysophosphatidic acid; LPC: lysophosphatidylcholine; MT1-MMP: membrane-type1 MMP; Pyk2: proline-rich tyrosine kinase; ROCK: Rho-kinase; SJ2: synaptojanin2; SPC: sphingosylphosphorylcholine; S1P: sphingosine-1-phosphate.

Figure 6.

RTK/PI3K/Akt signaling. The binding of RTK, including EGFR and PDGFR, by the p85 subunit of PI3K results in activation of the catalytic subunit (p110), which then catalyzes phosphorylation of PI 3,4-bisphosphate (PiP2) into 3,4,5-triphosphate (PiP3). Inversely, PTEN turns PiP3 into PiP2. PiP3 in turn activates phosphoinositide-dependent kinase-1 (PDK1), which phosphorylates Thr308 of Akt, while Ser473 of Akt is phosphorylated by mTORC2. Activated Akt then inactivates TSC1/TSC2 suppressor complex, which in turn activates mTORC1 as a result. The signaling pathway affects multiple cellular processes including cell survival, proliferation, and motility. Solid and dashed arrows indicate activation and suppression, respectively.

Figure 7.

The p53 pathway and retinoblastoma (RB) tumor suppressor protein signaling are shown. MDM2 and MDM4 are important negative regulators of the p53. p14^ARF inhibits MDM2, thus promoting p53. DNA damage activates ATM, which leads to activation of checkpoint kinases (CHK2) and p53. Solid and dashed arrows indicate activation and suppression, respectively. Activating genetic alterations are shown in red circle. Genetic alterations that lead to a loss of function are indicated in blue circle. Figure is modified from [121].

Figure 8.

RAS signaling. RAS proteins act as on/off (RAS-GDP/RAS-GTP) switches controlled by RTKs and NF-1. Activated RAS (RAS-GTP) then activates serine/threonine kinase RAF. RAF activates mitogen-activated protein kinase kinase (MAPKK), also called MEK, which in turn activates MAPK. MAPK activation results in activation of various transcription factors, such as Elk1, c-myc, Ets, STAT1/3, and PPARγ, which induce cell transformation and inhibit apoptosis. Solid and dashed arrows indicate activation and suppression, respectively. PPARγ: peroxisome proliferator-activated receptor γ, STAT: signal transducers and activators of transcription.

Figure 9.

Signaling pathway in glioma stem cell. BMP: bone morphogenetic proteins; BMPR: BMP receptor; Ptch: patched gene; SHH: Sonic hedgehog homolog; STAT: signal transducers and activators of transcription; Smo: smoothened gene; TNFAIP: tumor necrosis factor alpha-induced protein; TRRAP: transformation/transcription domain-associated protein.