gms | German Medical Science

The proto-oncogene encoded tyrosine kinase receptor MET and its ligand scatter factor/hepatocyte growth factor (SF/HGF) are strongly upregulated in malignant gliomas. The SF/HGF-MET system is important for glioma cell migration, invasion, proliferation and angiogenesis. We used a novel single-chain anti-MET antibody to inhibit glioblastoma growth in an orthotopic model.

U87 glioblastoma cells were xenografted into the brains of nude mice. On day 1 or day 7 after tumour cell injection osmotic minipumps with intratumoural catheters were implanted. The one-armed anti-MET antibody (40 μg/day) was infused intratumourally until 3 weeks after tumour cell injection. Tumour size, proliferation, apoptosis, microvessel density and expression of extracellular matrix (ECM) molecules were analysed by immunohistochemistry. cDNA arrays were performed to determine the effect of the anti-MET antibody on the expression of invasion-related genes in vitro. Functional effects of the anti-MET antibody were analysed in vitro.

The effects of the anti-MET treatment on tumour size and morphology were very similar, regardless whether treatment was initiated on day 1 or day 7. Tumour volumes were reduced by >95% (p<0.001) in animals treated with the anti-MET antibody compared with controls. Tumour cell proliferation was reduced by >75% (p<0.001) in treated tumours; microvessel density was reduced by >90% (p<0.001); the fraction of apoptosis was increased by >60% (p<0.05). Interestingly, the tumour cell density was >2-fold higher in controls than in treated tumours, in which a striking increase in ECM deposition between tumour cells was apparent. Immunohistochemically, strong increases in staining intensities for laminin, fibronectin and tenascin were found in tumours treated with the anti-MET antibody. cDNA arrays revealed downregulation of uPA, tPA, MMP7, MMP15 and MMP16 and upregulation of PAI-1 in U87 cells treated with the anti-MET antibody, which may explain the increase in ECM proteins in vivo. Proliferation and migration of U87 cells in vitro were inhibited by the anti-MET antibody.

Local treatment with the one-armed anti-MET antibody can inhibit intracerebral glioblastoma growth almost completely. The responsible mechanisms appear to include anti-proliferative, anti-angiogenic, anti-migratory and pro-apoptotic effects as well as enhancement of ECM deposition, presumably caused by decreased matrix degradation.