Inhibition of Intracerebral Glioblastoma Growth by Local Treatment with the Scatter Factor/Hepatocyte Growth Factor-Antagonist NK4
- Marc A. Brockmann,
- Apollon Papadimitriou,
- Michael Brandt,
- Regina Fillbrandt,
- Manfred Westphal and
- Katrin Lamszus1
- Department of Neurosurgery, University Hospital Hamburg-Eppendorf, 20246 Hamburg [M. A. B., R. F., M. W., K. L.], and Roche Diagnostics GmbH, Pharma Research Penzberg, 82372 Penzberg [A. P., M. B.], Germany
Abstract
Purpose: 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.
Experimental Design: 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.
Conclusion: 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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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This work was supported by a grant from the Erich and Gertrud Roggenbuck-Stiftung. M. A. B. was a scholar of the Jung-Stiftung für Wissenschaft und Forschung.
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↵1 To whom requests for reprints should be addressed, at Department of Neurosurgery, Laboratory for Brain Tumor Biology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Phone: 49-40-42803-5577; Fax: 49-40-42803-5982; E-mail: lamszus{at}uke.uni-hamburg.de
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↵2 The abbreviations used are SF/HGF, scatter factor/hepatocyte growth factor; FBS, fetal bovine serum; HUVEC, human umbilical vein endothelial cell; vWF, von Willebrandt factor; hpf, high power field.
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↵3 M. A. Brockmann et al., unpublished observations.
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- Accepted May 16, 1903.
- Received February 12, 1903.
- Revision received May 16, 1903.
