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Signaling Cascades Driving the Malignant Phenotype of Glioma Cells

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Glioma Cell Biology

Abstract

The most malignant brain tumor glioblastoma multiforme (GBM) is characterized by exponential growth and diffuse invasiveness. These characteristics are attributed to the varieties of common genetic lesions in genes encoding signaling proteins. These DNA damages lead to either activating mutations (Ras, PI3K, and Akt) or loss of function of tumor suppressor proteins (TP53, Rb, and PTEN). The signaling pathways induced by the altered signaling proteins play a role in the maintenance of the GBM malignant phenotype. Recent studies have elucidated various genetic alterations and critical signaling pathways involved in GBM. This has improved our understanding of GBM cell proliferation, migration, and invasion. Additionally, new exciting areas of research, such as stem cell biology and “-omics” analyses, have been recently employed for GBM studies. Many efforts are now directed to identification of signaling molecules involved in gliomagenesis and glioma stem cell maintenance. Signaling pathway analysis has resulted in novel GBM subclassifications that could integrate with conventional histopathological features providing information regarding the molecular mechanism of pathogenicity. The identification of aberrant signal transduction pathways and their role in glioma development and progression may contribute to the development of novel therapeutic targets. This chapter provides an overview of the current understanding of GBM oncogenomics, signaling pathways, and glioma stem cell signaling as well as the molecular circuitry regulating several key cellular processes.

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Abbreviations

ALK:

Activin receptor-like kinase

bFGF:

Basic fibroblast growth factor

BMP:

Bone marrow protein

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular signal-regulated kinase

Frz:

Frizzled receptor

GBM:

Glioblastoma multiforme

Gli:

Gliotactin

GSC:

Glioma stem cells

HB-EGF:

Heparin-binding EGF-like growth factor

IDH1:

Isocitrate dehydrogenase-1

IL-2:

Interleukin-2

iPS:

Induced pluripotent

JNK:

c-Jun N-terminal kinase

LIF:

Leukemia inhibitory factor

LIFR:

LIF receptor

MAPK:

Mitogen-activated protein kinase (ERK1 and ERK2)

MAPKK:

MAPK kinase

MMP:

Matrix metalloproteinase

NICD:

Intracellular domain of the Notch receptor

NSC:

Neural stem cell

PDGFRA:

Platelet-derived growth factor receptor A

PDK1:

Phosphoinositide-dependent kinase-1

PI3K:

Phosphatidylinositide-3-kinase

PIP3:

Phosphatidylinositol 3,4,5-trisphosphate

Ptch:

Patched homolog

PTEN:

Phosphatase and tensin homolog

RTK:

Receptor tyrosine kinase

Shh:

Sonic hedgehog

Smo:

Smoothened homolog

Sox2:

Sry-related HMG-Box factor 2

TCGA:

The Cancer Genome Atlas

TGF:

Transforming growth factor

TMZ:

Temozolomide

TNF-α:

Tumor necrosis factor-α

VEGFR:

Vascular endothelial cell growth factor receptor

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  1. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan

    Mitsutoshi Nakada, Daisuke Kita, Takuya Furuta, Takuya Watanabe, Yutaka Hayashi & Jun-Ichiro Hamada

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  1. Mitsutoshi Nakada
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  2. Daisuke Kita
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Correspondence to Mitsutoshi Nakada .

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  1. Biochemistry and Experimental Oncology, Charles University Prague 1st Faculty of Medicine, Prague, Czech Republic

    Aleksi Sedo

  2. Anatomisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Rolf Mentlein

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Nakada, M., Kita, D., Furuta, T., Watanabe, T., Hayashi, Y., Hamada, JI. (2014). Signaling Cascades Driving the Malignant Phenotype of Glioma Cells. In: Sedo, A., Mentlein, R. (eds) Glioma Cell Biology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1431-5_3

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