gms | German Medical Science

Objective: Angiogenesis is a promising target for anti-glioma therapy. Our former experiments proved the angiogenic switch to start even earlier than in grade III gliomas without a hint on the exact time point and localization. To stop angiogenesis as early as possible, we want to identify further marker molecules. Our results indicate for the first time that angiogenic changes occur as early as in WHO grade II gliomas within the glioma invasion zone that serves as direct interaction zone with the brain tissue.

Methods: Vessels of 118 gliomas were investigated for their microvessel density and for the expression of CD31, MMP2, PAR1 and ETS1. Endothelial cells were prepared and co-cultured with human glioblastoma cells, and their ETS1 expression was analysed immunochemically.

Results: CD31 is expressed on all endothelial cells and serves as internal control. The matrix-metalloproteinase 2 (MMP2) is upregulated in tumor blood vessels according to the WHO grade with the glioblastomas showing the strongest vascular MMP2 expression. The same is shown for the protease-activated receptor type 1 (PAR1) with the strongest expression in glioblastomas. Only ETS1 differs from this pattern. ETS1 is positively stained in activated endothelial cells in cell culture. Scratch wounds cause the rise of ETS1. Closure of the scratch wound decreases ETS1 subsequently. Endothelial cells co-cultured with glioblastoma cells increase their intracellular ETS1 level. Blood vessels of the low-grade glioma invasion zone show an increased ETS1 expression within endothelial cells. Smaller vessels of the invasion zone are significantly stronger positive than larger vessels. Blood vessels of the peritumoral edema zone and blood vessels of the tumor center show a significantly less ETS1 expression. The same is observed for the glioblastomas with the difference that also blood vessels of the tumor center are strongly ETS1 positive. Neither MMP2 and PAR1 nor ETS1 are observed in normal brain parenchyma blood vessels.

Conclusions: The expression of MMP2 and PAR1 is correlated to the WHO grade of gliomas. Whereas low-grade glioma microvessel density does not show a sign of tumor angiogenesis, their endothelial cells within the invasion zone strongly express ETS1. This proves ETS1 to be one of the first proteins to be increased before other indicators for angiogenesis are obvious. This makes ETS1 a putative target for anti-angiogenesis therapy.