Modulation of angiogenesis and tumorigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor.
Human melanoma cells express two prominent angiogenic factors, e.g., vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF/fibroblast growth factor-2). In this study, we report on the relative contribution of these two factors to in vitro and in vivo growth of a tumorigenic melanoma cell line (WM164) and nontumorigenic, immortalized melanocytes (FM516SV). Overexpression of either cytokine significantly boosted tumorigenicity of WM164 cells in immunodeficient SCID mice. Attempting to overexpress bFGF antisense sequences produced no viable clones confirming earlier reports that autocrine bFGF is obligatory to melanoma cell survival and growth. By contrast, down-regulation of endogenous VEGF production did not affect growth of WM164 cells in vitro. In vivo expansion of WM164 cells expressing VEGF antisense was delayed but not abrogated. Forced expression of either bFGF or VEGF in immortalized but nontumorigenic melanocytes did not induce sustained tumor growth in vivo highlighting that neither of the two factors is sufficient for induction of tumorigenicity in this model system. Overexpression of either cytokine in WM164 cells led to the development of atypical large vessels but not to an increase in microvessel density. Taken together our results confirm an essential autocrine role of bFGF in human melanoma and indicate a beneficial but nonessential role of VEGF in the tumorigenic phenotype of human melanoma cells.
Graeven
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U
Department of Medicine, Ruhr Universität Bochum, Knappschaftskrankenhaus, 44892 Bochum, Germany. ullrich.graeven@ruhr-uni-bochum.de
Rodeck
U
U
Karpinski
S
S
Jost
M
M
Philippou
S
S
Schmiegel
W
W
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008545:Melanoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2