In this review, we highlight progress made in the understanding of MET signaling in glioma and advances in therapies targeting HGF/MET molecules for glioma patients in recent years, in addition to studies on the expression and mutation status of MET.
This process amplifies hepatocyte growth factor (HGF)-mediated signaling and stimulates actin cytoskeleton dynamics that promote glioma cell migration.
Conversely, HGF/c-Met pathway inhibitors reduced Cyr61 expression in HGF(+)/c-Met(+) human glioma cell lines in vitro and in HGF(+)/c-Met(+) glioma xenografts.
These observations indicate that hypoxia is a key factor in determining NSC tropism to glioma and that SDF-1/CXCR4, uPA/uPAR, VEGF/VEGFR2, and hepatocyte growth factor/c-Met signaling pathways mediate increased NSC-to-glioma tropism under hypoxia.
These studies implicate DEAD/H box helicase 21, polycystin (PKD1) and amplified in breast cancer 1 as novel transcription-dependent regulators of scatter factor-mediated glioma cell protection against cytotoxic death, and identify other potential regulators for future study.
Clinical trials using novel SF/HGF/c-Met pathway inhibitors in glioma and other malignancies associated with c-Met activation should ultimate include concurrent radiation and potentially other cytotoxic therapeutics.
Since the Raf-PKC-MEK cascade is used for HGF's signaling via its receptor in astrocytoma cells, our data revealing similar regulatory mechanism for HGF secretion in these cells would help to explain the feed forward nature of HGF action in glioma cells that would further accentuate its basal secretion, exacerbating its effects on the progression of gliomas in an autocrine fashion.
Furthermore, we have defined a novel pathway for hepatocyte growth factor (HGF)-induced glioma cell migration and invasion which requires the induction of TGF-beta2 expression.
Several lines of evidence indicate that hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, may play an important role in progression of human glioma.
By contrast, the level of TIMP- 1 mRNAs was not altered significantly and that of TIMP-2 was reduced mildly by the HGF/SF treatment, suggesting that HGF/SF may eventually modulate a balance between MMP-2 and TIMPs in favor of the proteinase activity in the glioma cell microenvironment.
To assess the possible in vivo significance of these migration assays, we compared the chemotactic response of a glioma cell line to human brain cyst fluids and tumor extracts that contained high or low SF concentrations.
Subcutaneous 9L-SFglioma growth was also greater than that in controls, although the differences were more variable.SF-producing i.c. gliomas contained elevated levels of 48-kd urokinase (3.5-fold) and 92-kd type IV collagenase (2.8-fold), both enzymes that correlate with the malignant progression of human gliomas (p < 0.001).