Abstract
The inhibition of tumor angiogenesis could be an efficient therapeutic strategy for the treatment of malignant gliomas. Prominent neovascularization is induced by these tumors, and microvascular proliferation is a malignancy grading criterion. However, glioma cells can also invade the brain diffusely over long distances without necessarily requiring angiogenesis. Experimentally, it was shown that especially during early stages of growth in rodent brain, glioma cells can coopt the preexistent host vasculature to recruit their blood supply in the absence of neovascularization. This phenomenon was only observed in orthotopic models in which the tumor cells were implanted into the brain which is a densely vascularized environment, but not in subcutaneous models in which tumor cells are implanted into a virtual space. Using an orthotopic mouse model, we analyzed whether systemic anti-angiogenic therapy with an antibody against the vascular endothelial growth factor receptor-2 (VEGFR2) could inhibit intracerebral growth of xenografted human glioblastoma cells and what effect this treatment had on tumor morphology and invasiveness. We found that anti-angiogenic therapy inhibited tumor growth by 80% compared to buffer-treated controls. The intratumoral microvessel density was reduced by at least 40% in treated animals compared to controls. However, in mice treated with the anti-VEGFR-2 antibody, we noticed a striking increase in the number and total area of small satellite tumors clustered around the primary mass. These satellites usually contained central vessel cores, and tumor cells often had migrated along blood vessels over long distances to eventually reach the surface and spread in the subarachnoid space. Systemic anti-angiogenic therapy can thus apparently increase the invasiveness of gliomas in the orthotopic model. Tumor cell invasion was tightly associated with preexistent blood vessels, suggesting that increased cooption of the host vasculature could represent a compansatory mechanism that is selected for by inhibiting adequate tumor vascularization.
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Lamszus, K., Kunkel, P., Westphal, M. (2003). Invasion as limitation to anti-angiogenic glioma therapy. In: Westphal, M., Tonn, JC., Ram, Z. (eds) Local Therapies for Glioma Present Status and Future Developments. Acta Neurochirurgica Supplements, vol 88. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6090-9_23
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DOI: https://doi.org/10.1007/978-3-7091-6090-9_23
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