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Functional VEGF and VEGF receptors are expressed in human medulloblastomas

Department of Experimental Biomedical Sciences (M.L.S., B.M., M.O.), Department of Biological Chemistry (A.M.B., M.F.), and Department of Surgical and Oncological Sciences, Pathology Section (M.G.), University of Padua, 35121 Padua; and Department of Pediatrics, Division of Hematology-Oncology, University-Hospital of Padua, 35128 Padua (M.C., G.P., A.R.); Italy

Address correspondence to Angelo Rosolen, Department of Pediatrics, Division of Hematology-Oncology, University-Hospital of Padua, Via Giustiniani 3, 35128 Padua, Italy (angelo.rosolen{at}unipd.it).

Vascular endothelial growth factor (VEGF) is one of the key regulators of tumor neoangiogenesis. It acts through two types of high-affinity tyrosine kinase receptors (VEGF receptor-1 [VEGFR-1]/fms-related tyrosine kinase 1 [Flt-1] and VEGFR-2/kinase domain receptor [KDR]) expressed on endothelial cells. VEGFRs have also been detected on cancer cells, suggesting a possible autocrine effect of VEGF on their growth. We studied the expression of VEGF, VEGFR-1, and VEGFR-2 in human medulloblastoma cell lines (DAOY, D283Med, and D341Med) and investigated the possible autocrine mechanisms of VEGF on medulloblastoma cell proliferation. Reverse transcriptase PCR analysis showed the presence of VEGF and VEGFR mRNAs in all cell lines studied. Of the three VEGF isoforms, VEGF₁₂₁ and VEGF₁₈₉ were detected by Western blot analysis in all three medulloblastoma cell lines, whereas VEGF₁₆₅ was identified only in DAOY cells. Medulloblastoma cell lines expressed both VEGFR-1 and VEGFR-2. We also demonstrated expression of VEGF and its receptors in medulloblastoma tumor specimens. Exogenous VEGFR-2 inhibitor reduced the VEGF-dependent cell proliferation of DAOY and D283Med cells. In DAOY cells, VEGF₁₆₅ induced phosphorylation of VEGFR-2/KDR and of downstream proteins in the signal transduction pathway. These data suggest a possible autocrine role for VEGF in medulloblastoma growth. Targeting VEGF signaling may represent a new therapeutic option in the treatment of medulloblastoma.

Key Words: medulloblastoma • VEGF • VEGFRs