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Angiostatin suppresses malignant glioma growth in vivo
M Kirsch1, J Strasser, R Allende
1Brigham and Women's Hospital, Dana-Farber Cancer Institute, Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Human malignant gliomas are among the most malignant and most intensely vascularized solid tumors. Angiostatin, an internal fragment of plasminogen, was recently discovered as an endogenous inhibitor of tumor-related angiogenesis by selective inhibition of endothelial cell growth. Using xenograft transplants of rat and primary human glioma cells in immunodeficient mice we investigated the effects of systemic administration of angiostatin purified from human plasma on tumor growth. The rat C6 and 9L glioma and the human U87 glioma cell lines implanted either s.c. or intracranially in Swiss nude mice responded to angiostatin in a dose-dependent fashion with growth inhibition to 11% of controls (P < 0.01), without detectable signs of toxicity. The inhibition of treated tumors was accompanied by a marked reduction of vascularity to 38% of controls (P < 0.01) in the presence of an up to 6-fold increased apoptotic index (P < 0.01), consistent with the hypothesis that angiostatin acts tumoristatic by inhibiting tumor-induced endothelial cell proliferation. Expression analysis of growth factors in angiostatin-treated tumors revealed an up to 3-fold decrease in vascular endothelial growth factor-mRNA and an up to 4-fold increase in basic fibroblast growth factor-mRNA, as compared with untreated controls in rat gliomas (P < 0.01). This suggests that inhibition of the tumorigenic phenotype may be mediated in part by a downregulation of vascular endothelial growth factor expression within the tumor. Our data demonstrate that systemic administration of angiostatin efficiently suppresses malignant glioma growth in vivo. The tumoristatic activity against intracranial tumors independent of the blood brain barrier suggests that targeting the vascular compartment may offer novel therapeutic strategies against malignant gliomas.
Insights
Systemic angiostatin administration effectively inhibits malignant glioma growth in mice. This treatment reduces tumor vascularity and increases apoptosis, suggesting novel therapeutic strategies targeting tumor vasculature.
Area of Science:
- Oncology
- Angiogenesis Research
- Molecular Biology
Background:
- Malignant gliomas are highly aggressive, vascularized tumors.
- Angiostatin, a plasminogen fragment, inhibits endothelial cell growth and tumor angiogenesis.
- Effective treatments for malignant gliomas remain a significant challenge.
Purpose of the Study:
- To investigate the efficacy of systemic angiostatin administration on malignant glioma growth in vivo.
- To assess the impact of angiostatin on tumor vascularity, apoptosis, and growth factor expression.
- To explore angiostatin as a potential therapeutic strategy for gliomas.
Main Methods:
- Xenograft models using rat (C6, 9L) and human (U87) glioma cells in immunodeficient mice.
- Systemic administration of purified angiostatin.
- Analysis of tumor growth, vascularity, apoptosis, and gene expression (VEGF, bFGF).
Main Results:
- Angiostatin significantly inhibited glioma growth in a dose-dependent manner (11% of controls).
- Tumor vascularity was markedly reduced (38% of controls) with a 6-fold increase in apoptosis.
- Angiostatin treatment led to decreased vascular endothelial growth factor (VEGF) mRNA and increased basic fibroblast growth factor (bFGF) mRNA.
Conclusions:
- Systemic angiostatin administration demonstrates potent tumoristatic activity against malignant gliomas in vivo.
- Angiostatin's efficacy is linked to reduced tumor vascularity and increased apoptosis, potentially via VEGF downregulation.
- Targeting the tumor vascular compartment with angiostatin offers a promising therapeutic strategy for malignant gliomas, even those resistant to blood-brain barrier penetration.