Abstract
Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed.
Highlights
Hepatocyte growth factor (HGF), known as scatter factor (SF), is a secreted protein that is involved in paracrine cellular signaling
In the context of medulloblastoma, mesenchymal-epithelial transition factor (MET) activation leads to the expression of proteins such as matrix metalloproteinases and vascular endothelial growth factor, which are known for their important roles in tumor promotion through angiogenesis [104]
Specific focus was placed on malignant brain tumors, current targeted therapies, and strategies to cross the blood and brain barrier
Summary
Rodent models have been used to study HGF and MET functions in early embryonic development. Studies have found that mice lacking HGF and MET genes die in utero from severely impaired placentas and other organs [10]. HGF is critical to the development of the nervous system, functioning to spatially direct axonal development for sensory, sympathetic, parasympathetic, and cortical neurons [12,13]. Organ culture experiments have shown that HGF and MET regulate mesenchymal and epithelial interactions and are expressed on the two cell types, respectively [15]. The paracrine interactions subsequently drive epithelial growth, morphogenesis, and differentiation through the differential spatial expression of HGF and MET [16]
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