Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis

Abstract

The multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor tyrosine kinase c-Met have emerged as key determinants of brain tumor growth and angiogenesis. SF/HGF and c-Met are expressed in brain tumors, the expression levels frequently correlating with tumor grade, tumor blood vessel density, and poor prognosis. Overexpression of SF/HGF and/or c-Met in brain tumor cells enhances their tumorigenicity, tumor growth, and tumor-associated angiogenesis. Conversely, inhibition of SF/HGF and c-Met in experimental tumor xenografts leads to inhibition of tumor growth and tumor angiogenesis. SF/HGF is expressed and secreted mainly by tumor cells and acts on c-Met receptors that are expressed in tumor cells and vascular endothelial cells. Activation of c-Met leads to induction of proliferation, migration, and invasion and to inhibition of apoptosis in tumor cells as well as in tumor vascular endothelial cells. Activation of tumor endothelial c-Met also induces extracellular matrix degradation, tubule formation, and angiogenesis in vivo. SF/HGF induces brain tumor angiogenesis directly through only partly known mechanisms and indirectly by regulating other angiogenic pathways such as VEGF. Different approaches to inhibiting SF/HGF and c-Met have been recently developed. These include receptor antagonism with SF/HGF fragments such as NK4, SF/HGF, and c-Met expression inhibition with U1snRNA/ribozymes; competitive ligand binding with soluble Met receptors; neutralizing antibodies to SF/HGF; and small molecular tyrosine kinase inhibitors. Use of these inhibitors in experimental tumor models leads to inhibition of tumor growth and angiogenesis. In this review, we summarize current knowledge of how the SF/HGF:c-Met pathway contributes to brain tumor malignancy with a focus on glioma angiogenesis.

Enhanced Epidermal Growth Factor, Hepatocyte Growth Factor, and Vascular Endothelial Growth Factor Expression in Tuberous Sclerosis Complex

“…EGFR has been localized to radial glial cells in the embryonic ventricular zone and is a marker for those that differentiate into astrocytes. Both HGF and its tyrosine kinase receptor c-Met are expressed by stem cells in the subventricular zone, 29 and in view of the prior demonstration of stem cell markers such as nestin in tubers, 30 these growth factors could also serve to characterize tubers as phenotypically immature. Like EGFR, HGF and c-Met are expressed in human gliomas and are believed to function in cell proliferation and angiogenesis (for review see Abounader and Laterra 29 ).…”

Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

“…In the context of cancer, c-Met activation results primarily through activating mutations in its kinase domain, c-Met overexpression, or HGF overexpression by cancer cells and/or tumor-infiltrating stromal cells (4). HGF and c-Met overexpression predicts poor prognosis in certain systemic cancers and correlates with malignant grade and angiogenesis in glial neoplasms and with poor survival in medulloblastoma (14). Inhibiting HGF/c-Met signaling using receptor-specific kinase inhibitors, ribozymebased gene expression inhibition, and neutralizing monoclonal antibodies has potent antitumor effects in vivo and sensitizes experimental glioma xenografts to radiation therapy (15)(16).…”

Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling

“…Activation of cMet stimulates proliferation, survival and invasiveness of cancer cells through several signalling pathways mediated by phosphatidylinositol 3-kinase/Akt, Src, STAT3 and Ras/mitogen-activated protein kinase (MAPK) 8 . In the vasculature, cMet activation through paracrine signalling by tumour cell-released HGF stimulates tumour angiogenesis by inducing proliferation, migration and survival of endothelial cells 13 . Expression of both cMet and HGF is induced by hypoxiainducible factor 1a, further providing evidence for an important role of the HGF/cMet axis in adverse microenvironment conditions to promote tumour angiogenesis 14,15 .…”