Brain Tumor Pathology

, Volume 21, Issue 2, pp 69–73

Angiogenesis and antiangiogenic therapy for malignant gliomas

  • Shingo Takano
  • Hiroshi Kamiyama
  • Koji Tsuboi
  • Akira Matsumura
Special Article


Angiogenesis is crucial to the growth of malignant gliomas. Therefore, antiangiogenic therapy represents a new, promising therapeutic modality for malignant gliomas. This study was designed to define the malignant glioma cases most suitable for antiangiogenic therapy in humans and to demonstrate the efficacy of antiangiogenic therapy in animals. Protein expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF), and its specific natural inhibitor, soluble Flt-1, as well as vessel architecture, including vessel density, area, and diameter, was evaluated in human malignant glioma samples (24 glioblastomas, 13 anaplastic astrocytomas). Among these, VEGF >1000ng/ml, VEGF/soluble Fltl ratio >1, vessel density >30, and vessel area >7% were prognostic factors for malignant gliomas. Based on these results, we per formed three different antiangiogenic experiments targeted to inhibit VEGF expression in a human malignant glioma (U87) mouse model: anti-VEGF neutralized antibody intraperitoneal injection; interferon-beta intramusclar injection; and transfection of an endogenous nonspecific angiogenesis inhibitor, thrombospondin-1, into glioma cells caused inhibition of VEGF secretion and/or mRNA expression and resulted in glioma growth inhibition of 70%, 84%, and 50%, respectively, compared with control. We conclude that malignant gliomas with high degrees of VEGF expression and vessel areas are good candidates for antiangiogenic therapy, especially that designed to inhibit VEGF expression.

Key words

Glioma Angiogenesis VEGF Soluble VEGF receptor Thrombospondin-1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Godard S, Getz G, Delorenzi M, et al (2003) Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res 63:613–6625Google Scholar
  2. 2.
    Jensen RL (1998) Growth factor-mediated angiogenesis in the malignant progression of glial tumors: a review. Surg Neurol 49:189–196PubMedCrossRefGoogle Scholar
  3. 3.
    Zagzag D, Amirnovin R, Greco MA, et al (2000) Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80:837–849PubMedGoogle Scholar
  4. 4.
    Lund E, Spang-Thomsen M, Skovgaard-Poulsen H, et al (1998) Tumor angiogenesis — a new therapeutic target in gliomas. Acta Neurol Scand 97:52–62PubMedCrossRefGoogle Scholar
  5. 5.
    Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nature Rev Cancer 2:727–739CrossRefGoogle Scholar
  6. 6.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364PubMedCrossRefGoogle Scholar
  7. 7.
    Kirsch M, Strasser J, Allende R, et al (1998) Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 58:4654–4659PubMedGoogle Scholar
  8. 8.
    Reed TA, Sorensen DR, Mahesparan R, et al (2001) Local endostatin treatment of gliomas administered by microcapsulated producer cells. Nat Biotechnol 19:29–34CrossRefGoogle Scholar
  9. 9.
    Takano S, Tsuboi K, Matsumura A, et al (2003) Anti-vascular endothelial growth factor antibody and nimustine as combined therapy: effects on tumor growth and angiogenesis in human glioblastoma xenografts. Neurooncol 5:1–7Google Scholar
  10. 10.
    Takano S, Yoshii Y, Kondo S, et al (1996) Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res 56:2185–2190PubMedGoogle Scholar
  11. 11.
    Lamszus K, Ulbricht U, Matschke J, et al (2003) Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 9:1399–1405PubMedGoogle Scholar
  12. 12.
    Yang JC, Haworth L, Sherry RM, et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434PubMedCrossRefGoogle Scholar
  13. 13.
    Bocci G, Francia G, Man S, et al (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922PubMedCrossRefGoogle Scholar
  14. 14.
    Tanaka T, Cao Y, Folkman J, et al (1998) Viral vector mediated “anti-angiogenic” gene therapy utilizing angiostatin cDNA. Cancer Res 58:3362–3369PubMedGoogle Scholar
  15. 15.
    Yoshida JA, Kajita T, Wakabayashi T, et al (1994) Long-term follow-up results of 175 patients with malignant glioma: importance of radical tumour resection and postoperative adjuvant therapy with interferon, ACNU and radiation. Acta Neurochir (Wien) 127:55–59CrossRefGoogle Scholar
  16. 16.
    Yoshida J, Mizuno M, Fujii M, et al (2004) Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Hum Gene Ther 15:77–86PubMedCrossRefGoogle Scholar
  17. 17.
    Singh RK, Gutman M, Bucana CD, et al (1995) Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci USA 92:4562–4566PubMedCrossRefGoogle Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2004

Authors and Affiliations

  • Shingo Takano
    • 1
  • Hiroshi Kamiyama
    • 1
  • Koji Tsuboi
    • 1
  • Akira Matsumura
    • 1
  1. 1.Department of Neurosurgery, Institute of Clinical MedicineUniversity of TsukubaIbarakiJapan

Personalised recommendations