VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors

Andreas Zielke, Martin Middeke, Sebastian Hoffmann, Mario Colombo-Benkmann, Peter Barth, Iyad Hassan, Annette Wunderlich, Lorenz C. Hofbauer, Quan Yang Duh, Bertil Hamberger, Fiemu Nwariaku, Andrea Frilling, W. Bradford Carter, Bradford Mitchell, Janice L. Pasieka

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Background. Pheochromocytomas are well-vascularized tumors of the adrenal medulla. In human pheochromocytomas, angiogenesis has been associated with tumor progression. The mechanisms, however, are unknown. Methods. Surgical specimens of benign, invasive, and metastatic human pheochromocytomas (n = 10/5/5) were immunostained for vascular endothelial growth factor (VEGF) and CD34, to determine VEGF expression and microvessel density (vascular surface density, [VSD]). In PC12-pheochromocytoma cells, VEGF messenger RNA and protein were analyzed by Northern blotting and enzyme immunoassay; biologic activity by human umbilical vein endothelial cell-proliferation assay. Inhibition of angiogenesis of PC12 xenografts by 2 neutralizing anti-VEGF antibodies (C20-pAB, M461-mAB) was evaluated by VEGF expression, VSD, and mitotic activity. Results. VEGF expression and VSD were significantly higher in metastatic pheochromocytomas (VEGF 37.1 ± 10.9% vs 20.7 ± 9%, VSD 26.2 ± 8 vs 13.5 ± 3.3 1/mm). VEGF messenger RNA and protein were confirmed in PC12 cells and stimulated by nerve growth factor. Conditioned PC12 medium increased human umbilical vein endothelial cell proliferation more than 2-fold. Xentrotransplanted PC12 cells had marked VEGF expression and angiogenesis, which was inhibited by anti-VEGF antibodies (VEGF-expression by 29 and 38%, VSD by 43 and 46%, P < .05). Conclusion. Higher VEGF expression and microvessel density in malignant pheochromocytomas suggest VEGF-mediated angiogenesis to be related to tumor progression. Angiogenesis of PC12 xenografts is mediated by VEGE Neutralizing anti-VEGF antibodies inhibit angiogenesis in experimental pheochromocytomas and may have potential for treating nonresectable pheochromocytomas.

Original languageEnglish (US)
Pages (from-to)1056-1063
Number of pages8
JournalSurgery
Volume132
Issue number6
DOIs
StatePublished - Dec 1 2002

ASJC Scopus subject areas

  • Surgery

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