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Review
. 2017 Jul 11;9(7):87.
doi: 10.3390/cancers9070087.

Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

Nichola Cruickshanks  1 , Ying Zhang  2 , Fang Yuan  3 , Mary Pahuski  4 , Myron Gibert  5 , Roger Abounader  6
Affiliations
Review

Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

Nichola Cruickshanks et al. Cancers (Basel). .

Abstract

Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described.

Keywords: Glioblastoma; HGF; MET.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of mesenchymal epithelial transition (MET) activation and current therapeutic strategies for hepatocyte growth factor (HGF)/MET inhibition. The MET receptor is activated through ligand (HGF) binding, which induces receptor dimerization and cross phosphorylation. Activation can be inhibited in several ways: (1) Decoy MET protein sequesters HGF from MET, (2) Anti-HGF and MET monoclonal antibodies competitively bind to the ligand and receptor, respectively. (3) HGF antagonists competitively bind to MET. (4) Small molecule kinase inhibitors prevent receptor activation by inhibiting kinase domain activity. (5) Gene therapy modulates HGF and MET mRNA production.
Figure 2
Figure 2
MET regulated signaling pathways implicated in the hallmarks of cancer. MET activation initiates the following downstream pathways: (1) phosphoinositide 3-kinase (PI3K) signaling conferring enhanced survival, (2) RAS/mitogen-activated protein kinase (MAPK) Pathway signaling resulting in enhanced proliferation, cell motility and invasion, (3) Jun amino-terminal kinases (JNK)/signal transducer and activator of transcription (STAT) signaling, which contributes to cell transformation and (4) focal adhesion kinase (FAK) signaling leading to increased cell motility and invasion.
Figure 3
Figure 3
Modes of deregulation of HGF/MET in cancer: (1) Autocrine and paracrine overexpression of HGF, (2) Amplification of MET gene leading to MET protein overexpression, (3) An activating mutation resulting in a constitutively active protein product, (4) HGF overexpression by tumor cells activating MET in the tumor microenvironment.
See this image and copyright information in PMC

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