Interferon-β (IFN-β) has been used clinically for
malignant glioma growth inhibition. Recently IFN-β is re-evaluated for its sensitization mechanism to the chemotherapeutic agent
temozolomide, because angiogenesis is essential for
malignant glioma growth. In this study, we investigated new mechanisms of inhibition of
glioma angiogenesis by IFN-β. Three
malignant glioma cell lines, U87, TK2 and Becker, were used for in vitro study. The effect of IFN-β for these cell lines were evaluated by means of proliferation (MTT assay),
conditioned medium induced HUVEC migration,
VEGF and
interferon inducible protein 10 (IP10,
angiogenesis inhibitor) expression by RT-PCR and western blot analysis. SCID mouse U87 subcutaneous model and U87 implant cranial window model were used for in vivo study. The effect of IFN-β with the models was evaluated by means of
tumor growth,
tumor tissue expression for
VEGF and IP10,
tumor tissue CD31 positive vessel densities, apoptosis and
tumor microcirculation (blood velocity, interaction between leukocytes and endothelial cells). In vitro, IFN-β upregulated IP10 expression and downregulated
VEGF expression time- (4-48 h) and dose- (10-5,000 U/ml) dependently. At the same dose,
glioma cell-induced HUVEC migration was inhibited, but cell proliferation was not affected. IFN-β local and systemic injection at 105 U and at 5x10(5) U/day, for 15 days inhibited U87 subcutaneous growth significantly. In the
tumor tissues,
VEGF expression and vessel densities were downregulated, but IP10 expression and apoptosis index upregulated. In addition, IFN-β local injection increased
collagen fiber deposition in the
tumor tissues. IFN-β 5x10(5) U/day, s.c. injection for 7 days reversed the decreased leukocyte adhesion to endothelial cells, but did not affect blood velocity and vessel images. One of the important roles of IFN-β for
malignant glioma growth inhibition was anti-angiogenesis by directly inhibiting angiogenesis through downregulation of
VEGF and upregulation of IP-10 and indirectly changing the
tumor microcirculation and regulating the interstitial pressure.