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

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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

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Pheochromocytoma
Vascular Endothelial Growth Factor A
Antibodies
Neoplasms
Blood Vessels
PC12 Cells
Human Umbilical Vein Endothelial Cells
Microvessels
Heterografts
Cell Proliferation
Messenger RNA
Adrenal Medulla
Nerve Growth Factor
Conditioned Culture Medium
Immunoenzyme Techniques
Northern Blotting
Proteins

ASJC Scopus subject areas

  • Surgery

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Zielke, A., Middeke, M., Hoffmann, S., Colombo-Benkmann, M., Barth, P., Hassan, I., ... Pasieka, J. L. (2002). VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors. Surgery, 132(6), 1056-1063. https://doi.org/10.1067/msy.2002.128613

VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors. / Zielke, Andreas; Middeke, Martin; Hoffmann, Sebastian; Colombo-Benkmann, Mario; Barth, Peter; Hassan, Iyad; Wunderlich, Annette; Hofbauer, Lorenz C.; Duh, Quan Yang; Hamberger, Bertil; Nwariaku, Fiemu; Frilling, Andrea; Carter, W. Bradford; Mitchell, Bradford; Pasieka, Janice L.

In: Surgery, Vol. 132, No. 6, 01.12.2002, p. 1056-1063.

Research output: Contribution to journalArticle

Zielke, A, Middeke, M, Hoffmann, S, Colombo-Benkmann, M, Barth, P, Hassan, I, Wunderlich, A, Hofbauer, LC, Duh, QY, Hamberger, B, Nwariaku, F, Frilling, A, Carter, WB, Mitchell, B & Pasieka, JL 2002, 'VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors', Surgery, vol. 132, no. 6, pp. 1056-1063. https://doi.org/10.1067/msy.2002.128613
Zielke, Andreas ; Middeke, Martin ; Hoffmann, Sebastian ; Colombo-Benkmann, Mario ; Barth, Peter ; Hassan, Iyad ; Wunderlich, Annette ; Hofbauer, Lorenz C. ; Duh, Quan Yang ; Hamberger, Bertil ; Nwariaku, Fiemu ; Frilling, Andrea ; Carter, W. Bradford ; Mitchell, Bradford ; Pasieka, Janice L. / VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors. In: Surgery. 2002 ; Vol. 132, No. 6. pp. 1056-1063.
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title = "VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors",
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.",
author = "Andreas Zielke and Martin Middeke and Sebastian Hoffmann and Mario Colombo-Benkmann and Peter Barth and Iyad Hassan and Annette Wunderlich and Hofbauer, {Lorenz C.} and Duh, {Quan Yang} and Bertil Hamberger and Fiemu Nwariaku and Andrea Frilling and Carter, {W. Bradford} and Bradford Mitchell and Pasieka, {Janice L.}",
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T1 - VEGF-mediated angiogenesis of human pheochromocytomas is associated to malignancy and inhibited by anti-VEGF antibodies in experimental tumors

AU - Zielke, Andreas

AU - Middeke, Martin

AU - Hoffmann, Sebastian

AU - Colombo-Benkmann, Mario

AU - Barth, Peter

AU - Hassan, Iyad

AU - Wunderlich, Annette

AU - Hofbauer, Lorenz C.

AU - Duh, Quan Yang

AU - Hamberger, Bertil

AU - Nwariaku, Fiemu

AU - Frilling, Andrea

AU - Carter, W. Bradford

AU - Mitchell, Bradford

AU - Pasieka, Janice L.

PY - 2002/12/1

Y1 - 2002/12/1

N2 - 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.

AB - 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.

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DO - 10.1067/msy.2002.128613

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