EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AND ITS RECEPTORS INTHE ANAPLASTIC PROGRESSION OF ASTROCYTOMA, OLIGODENDROGLIOMA, AND EPENDYMOMA

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angio genic factor, which is known to be upregulated in most cases of gliobl astoma multiforme (GBM). The expression of VEGF and its receptors in e pendymomas, oligodendrogliomas, and particularly the expression during anaplastic progression of these three types of gliomas has not been s tudied extensively. Fifty-six gliomas, consisting of 10 ependymomas, 1 2 oligodendrogliomas, 3 anaplastic oligodendrogliomas, 6 astrocytomas grade II, 5 anaplastic astrocytomas, and 20 glioblastoma multiformes, were investigated for VEGF and receptor expression using in situ hybri dization (ISH) and reverse transcription polymerase chain reaction (RT -PCR). Results showed that VEGF was moderately to strongly expressed i n 8 of 10 ependymomas and in all anaplastic oligodendrogliomas and gli oblastoma multiforme cases. These tumors displayed similar degrees of extensive necrosis and vascular proliferation, with VEGF expression co nsistently seen in tumor cells around necrotic areas. The VEGF express ion, although present at a lower level, also was shown in 4 of 12 olig odendrogliomas, in 3 of 6 astrocytomas grade II, and in 2 of 5 anaplas tic astrocytomas, with a regional rather than diffuse pattern of posit ive result. The findings from the in situ hybridization study correlat ed with the expression index, as determined by reverse transcription p olymerase chain reaction. Expression of VEGF was correlated significan tly with vascular proliferation (p < 10(-5)) and necrosis (p < 10-5), as well as with microvessel density (p = 0.002, r(s) = 0.41). The VEGF receptors, kinase domain region (KDR) and Fms-like-tyrosine kinase (F lt-1), also were upregulated in the tumor vasculature of glioblastoma multiforme, anaplastic oligodendrogliomas, and ependymomas with necros is; whereas the astrocytomas grade II, anaplastic astrocytomas, and ol igodendroglioma tumors tended to express a weak to nondetectable signa l. Anaplastic progression in all three types of gliomas is heralded by the occurrence of small zones of VEGF-expressing cells and early vasc ular proliferation, followed by an accelerated phase of angiogenesis c losely associated with VEGF induction around areas of necrosis and wit h the expression of VEGF receptors in the tumor vasculature.