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Basic and Translational Investigations |
Departments of Neurological Surgery (R.D., C.P., K.L., P.L., A.H., H.S., S.V., G.B.) and Pathology (S.V.) and Brain Tumor Research Center and Comprehensive Cancer Center (C.P., G.B.), University of California San Francisco, San Francisco, CA, USA; Department of Neurological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA (R.D.); Western Australian Institute for Medical Research, Perth, Australia (R.G.)
Address correspondence to Gabriele Bergers, University of California San Francisco, Department of Neurological Surgery, 513 Parnassus Ave., Box 0520, San Francisco, CA 94143-0520, USA (gabriele.bergers{at}ucsf.edu).
Glioblastoma multiforme (GBM) is one the most aggressive brain tumors due to the fast and invasive growth that is partly supported by the presence of extensive neovascularization. The matrix metalloproteinase MMP-2 has been associated with invasive and angiogenic properties in gliomas and is a marker of poor prognosis. Since MMP-2 is expressed in both tumor cells and endothelial cells in GBM, we generated genetically engineered MMP-2 knockout (MMP-2ko) GBM to examine the importance of the spatial expression of MMP-2 in tumor and/or normal host-derived cells. MMP-2–dependent effects appeared to be dose-dependent irrespective of its expression pattern. GBM completely devoid of MMP-2 exhibited markedly increased vascular density associated with vascular endothelial growth factor receptor 2 (VEGFR2) activation and enhanced vascular branching and sprouting. Surprisingly, despite the high vascular density, tumor cells were more prone to apoptosis, which led to prolonged survival of tumor-bearing mice, suggesting that the increased vascularity is not functional. Congruently, tumor vessels were poorly perfused, exhibited lower levels of VEGFR2, and did not undergo proper maturation because pericytes of MMP-2ko tumors were not activated and were less abundant. As a result of impaired and dysfunctional angiogenesis, MMP-2ko GBM became more invasive, predominantly by migrating along blood vessels into the brain parenchyma.
Key Words: angiogenesis • glioblastoma multiforme • invasion • matrix metalloproteinase-2 • survival
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