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Review
. 2020 Oct 4;12(10):2860.
doi: 10.3390/cancers12102860.

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

Filippo Torrisi  1 , Nunzio Vicario  1 , Federica M Spitale  1 , Francesco P Cammarata  2 , Luigi Minafra  2 , Lucia Salvatorelli  3 , Giorgio Russo  2 , Giacomo Cuttone  4 , Samuel Valable  5 , Rosario Gulino  1 , Gaetano Magro  3 , Rosalba Parenti  1
Affiliations
Review

The Role of Hypoxia and SRC Tyrosine Kinase in Glioblastoma Invasiveness and Radioresistance

Filippo Torrisi et al. Cancers (Basel). .

Abstract

Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment.

Keywords: Glioblastoma; SRC tyrosine kinase; hypoxia; invasion; radioresistance; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Glioblastoma, isocitrate dehydrogenase (IDH) wildtype. Highly anaplastic glial cells with nuclear atypia and pleomorphism (a); palisading necrosis (arrows) and microvascular proliferation (b); at immunohistochemistry the neoplastic cells show a high proliferation index (Ki67); (c) no immunostaining for IDH-1; (d) and retained ATRX chromatin remodeler (ATRX) (e).
Figure 2
Figure 2
Schematic representation of SRC structure and regulation. The inactive form of SRC is illustrated on the left side, with the specification of each SH domain; in this closed conformation, the phosphorylation of Tyr530 on C-terminal creates a link with the SH2 and the catalytic site, which is positioned on SH1, becoming not accessible for the substrates. In the transition to the active form, the phosphorylation of Tyr419 is showed with the main pathways that act by downstream and upstream effectors. The conformational switch is mediated by many phosphatases, such as PTPα, PTPγ, SHP-1 and -2, and PTP1B, able to dephosphorylate SRC. The regulation of activated SRC is displayed with the RTKs and integrins signaling. In particular, the downstream effectors of RTKs/SRC interaction lead to target genes transcription for survival, proliferation, and angiogenesis sustainment. The interaction of integrins with ECM components and their localization on cell adhesion sites, determines the modulation of cell motility: The SRC signaling pathway induces a cascade that results in the phosphorylation of several proteins, such as FAK, talin, and paxillin, with the final actin cytoskeleton regulation that is responsible for migration and invasion mechanisms.
Figure 3
Figure 3
Schematic representation of the main pathways for the invasion process induced by hypoxia. SRC pathway stimulation under hypoxia contributes to the deregulation of the principal events required for invasion, including cell adhesion, activation of cell motility, and production of proteolytic enzymes.
See this image and copyright information in PMC

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