gms | German Medical Science

Objective: Human astrocytic brain tumors consist of a heterogeneous group of neoplasms ranging from WHO grade I to IV. A major hallmark of malignant progression in high-grade astrocytomas – especially glioblastoma (GBM) – is the formation of new blood vessels which is mainly promoted by vascular endothelial growth factor (VEGF) that acts via ist receptors VEGFR-1-3 and their co-receptors neuropilin (NRP) -1 and -2. The inhibition of the VEGF-pathway leads to reduced tumor growth in vitro and in vivo in animal models. Apart from established treatment procedures including surgery, chemotherapy and radiation, additional anti-angiogenic therapy strategies e.g. using the monoclonal anti-VEGF-antibody Bevacizumab are already in use for several cancer entities. Bevacizumab treatment leads to an increased progression-free survival rate in GBM patients but does not influence the overall survival. However, to date it is unclear why the anti-angiogenic therapy fails in most GBM patients while a small sub-population strongly profits from this treatment. Therefore, the aim of our study was to determine the VEGF- and VEGFR-status in a large cohort of glioma patients and ist association with tumor grade and patient survival.

Method: We investigated 344 astrocytoma patients including 46 pilocytic astrocytomas (WHO grade I), 13 diffuse astrocytomas (WHO grade II), 33 anaplastic astrocytomas (WHO grade III) and 252 glioblastomas (WHO grade IV) patients for the expression of VEGF-A, VEGFR-1-3 and NRP-1-2 by immunohistochemistry. For VEGF-A, we additionally performed in-situ hybridization.

Results: Apart from NRP-2 we found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal appearing brain tissue (p<0.001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1-2 and NRP-1 levels when compared to WHO grade II and III astrocytomas (p<0.01) but lower levels than glioblastomas. The expression of NRP-2 was low in all tumors. We did not find a significant correlation between protein expression and patient survival for each factor and WHO grade.

Conclusions: Our findings of heterogeneous expression of VEGF and its receptors indicate that a careful testing for the VEGF-receptor levels in glioma patients receiving anti-angiogenic treatment should be performed since the target of therapy may not be present in all cases.