High-Level Expression of Angiogenic Factors Is Associated with Advanced Tumor Stage in Human Neuroblastomas1
- Angelika Eggert2,
- Naohiko Ikegaki,
- Janet Kwiatkowski,
- Huaqing Zhao,
- Garrett M. Brodeur and
- Bruce P. Himelstein
Abstract
Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. Neuroblastoma (NB) is a common pediatric tumor of neural crest origin, which is biologically and clinically heterogeneous. Increased tumor vascular index correlates with poor outcome of NB. To determine which angiogenic factors contribute to NB angiogenesis and thereby support tumor progression, we examined the expression of eight angiogenic factors [vascular endothelial growth factor (VEGF), VEGF-B, VEGF-C, basic fibroblast growth factor, angiopoietin (Ang)-1, Ang-2, transforming growth factorα , and platelet-derived growth factor (PDGF)] by semiquantitative RT-PCR in 37 NB primary tumors and in 22 NB cell lines. We also analyzed the relationship between angiogenic factor expression and clinicopathological factors as well as patient survival. All eight angiogenic factors examined were expressed at various levels in NB cell lines and tumors, suggesting their involvement in NB angiogenesis. The expression levels of most angiogenic factors were correlated with each other, suggesting their synergy in regulating the angiogenic process. Significantly higher expression levels of VEGF, VEGF-B, VEGF-C, basic fibroblast growth factor, Ang-2, transforming growth factor α, and PDGF-A (P < 0.0001–0.026) were found in advanced-stage tumors (stages 3 and 4) compared with low-stage tumors (stages 1, 2, and 4S). Expression of PDGF-A was significantly associated with patient survival (P = 0.04). The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 Supported by grants from the Dr. Mildred Scheel-Stiftung (to A. E.), the NIH Grant NS 34514 (to G. M. B.), the Audrey E. Evans Endowed Chair (to G. M. B), and the W. W. Smith Charitable Trust (to B. P. H.)
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↵2 To whom requests for reprints should be addressed, at Children’s Hospital of Philadelphia, Division of Oncology, ARC Room 902, 3516 Civic Center Boulevard, Philadelphia, PA 19104. Phone: (215) 590-4855; Fax: (215) 590-3770; E-mail: eggert{at}email.chop.edu
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↵3 VEGF, vascular endothelial growth factor; bFGF, basic fibroblast factor; TGF-α, transforming growth factor α; PDGF, platelet-derived growth factor; Ang, angiopoietin; NB, neuroblastoma; RT, reverse transcription.
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↵4 Eggert, A., Brodeur, G. M., Ikegaki, N. A relative quantitative RT-PCR protocol for TrkB expression in neuroblastoma using GAPD as an internal control. Biotechniques, 28: in press, 2000.
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- Accepted February 24, 1900.
- Received November 22, 1999.
- Revision received February 15, 1900.
