Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte growth factor-antagonist NK4.
OBJECTIVE
Scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor MET are strongly up-regulated in malignant gliomas. The SF/HGF-MET system contributes to glioma invasion and angiogenesis via autocrine and paracrine mechanisms. We analyzed whether local treatment with NK4, an antagonistic fragment of SF/HGF, could inhibit glioma growth in vivo.


METHODS
A guide-screw system was used to implant tumor cells intracerebrally and to perform therapeutic injections. Mice received daily intratumoral injections of NK4 or buffer as of day 1 or 7 after tumor cell injection until day 20. Functional effects of NK4 on glioma and endothelial cells were analyzed in vitro.


RESULTS
Tumor volume was reduced by 61.1% in mice treated with NK4 compared with controls when treatment was initiated on day 1 (P < 0.05) and by 61.4% when treatment was initiated on day 7 (P < 0.001). Intratumoral microvessel density was reduced by 64.9% when treatment started on day 1 and by 36.7% when it started on day 7. The proliferative activity of the tumor cells was reduced by >30% regardless of when NK4-treatment was initiated. The apoptotic fraction of tumor cells was increased 2-fold and 1.5-fold when animals were treated with NK4 as of day 1 or day 7, respectively. In vitro, NK4 inhibited SF/HGF-induced glioblastoma, and endothelial cell migration and proliferation in a dose-dependent fashion.


CONCLUSIONS
NK4 inhibits glioblastoma growth in vivo, most likely via antimitogenic, antimotogenic, proapoptotic, and antiangiogenic mechanisms. Given the strong up-regulation of SF/HGF and MET in human malignant gliomas, NK4 holds promise as a direct interstitial therapeutic agent for these fatal tumors.
Brockmann
Marc A
MA
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.
Papadimitriou
Apollon
A
Brandt
Michael
M
Fillbrandt
Regina
R
Westphal
Manfred
M
Lamszus
Katrin
K
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use*; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D008934:Mitogens; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D015996:Survival Rate; D014407:Tumor Cells, Cultured
C066855:HGF protein, human; D008934:Mitogens; D017228:Hepatocyte Growth Factor