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Abstract
Two prominent biological features of the advanced stages of human melanoma are their high degree of vascularity and high-level expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1). Given these characteristics, human melanoma serves as an ideal model to address an important question regarding the efficacy of angiogenesis-based cancer therapy. To induce tumor growth arrest and regression, does it suffice to block expression of bFGF and/or FGFR-1 in only the melanoma cells, or is it essential to inhibit expression of bFGF and/or FGFR-1 in both the melanoma cells and the melanoma cell-interspersing vasculature? Primary and metastatic human melanomas, grown as subcutaneous tumors in nude mice, were injected twice a week with vector constructs containing the human tyrosinase promoter and antisense- oriented human bFGF or FGFR-1 cDNA. On alternating days, the bFGF and FGFR-1 antisense-targeted tumors received injections of cyanine fluorochrome-conjugated antibodies to a human melanoma and mouse blood vessel marker. Noninvasive, dynamic fluorescence imaging was used to document the cellular events that took place inside the tumors as the result of blocking expression of bFGF or FGFR-1 in the melanoma cells. In vivo, ex vivo, and in vitro fluorescence imaging of the bFGF and FGFR-1 antisense-targeted tumors demonstrated that inhibiting bFGF and FGFR-1 signaling in only the melanoma cells suffices to inhibit tumor growth due to massive induction of melanoma cell apoptosis. The investigations presented in this study document that inhibiting expression of bFGF or FGFR-1 in only the melanoma cells is as effective in blocking tumor growth as simultaneously inhibiting bFGF or FGFR-1 synthesis in the melanoma cells and the melanoma cell-interspersing vasculature. Furthermore, blocking expression of bFGF or FGFR-1 in the melanoma cells did not lead to activation or increased production of another angiogenic molecule, suggesting the absence of a "salvage pathway" that can circumvent or rescue the blockage of bFGF/FGFR-1 in the melanoma cells.
Highlights
Unlike normal melanocytes, primary melanomas in the vertical growth phase (VGP) and melanomas in the metastatic growth phase (MGP) express high levels of basic fibroblast growth factor and fibroblast growth factor receptor-1 (FGFR-1)
104 Molecular Medicine, Volume 8, Number 2, February 2002 injected with human tyrosinase (Tyr), Rous Sarcoma Virus (RSV) promoter-driven basic fibroblast growth factor (bFGF), or FGFR-1 antisense construct and fluorochrome-conjugated antibodies to a human melanoma and mouse blood vessel marker, the findings presented here demonstrate that antisense targeting of bFGF and, likewise, FGFR-1 in only the melanoma cells is as effective in inhibiting tumor growth as blocking expression of bFGF and FGFR-1 simultaneously in the melanoma cells and the melanoma cell-interspersing blood vessels
To obtain a more detailed insight into regulation of melanoma angiogenesis, addressing in particular the issue of potential “cross-talk” between bFGF/ FGFR-1 produced by melanoma cells and angiogenic molecules emanating from endothelial cells lining the melanoma-interspersing vasculature, we replaced the RSV promoter in the bFGF and FGFR1 antisense-oriented plasmid with a 430-bp cDNA fragment of the human tyrosinase promoter [8], which is strongly expressed in cells of the human melanocytic lineage
Summary
Primary melanomas in the vertical growth phase (VGP) and melanomas in the metastatic growth phase (MGP) express high levels of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1). Antisense targeting of bFGF/FGFR-1 in VGP and MGP melanomas, grown as subcutaneous tumors in nude mice, demonstrated inhibition of tumor growth and regression as a result of blocked intratumoral angiogenesis [4]. Given these findings, the present study was designed to address two important, yet unresolved questions with respect to potential angiogenesis-based melanoma therapy. Two prominent biological features of the advanced stages of human melanoma are their high degree of vascularity and high-level expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) Given these characteristics, human melanoma serves as an ideal model to address an important question regarding the efficacy of angiogenesis-based cancer therapy. Blocking expression of bFGF or FGFR-1 in the melanoma cells did not lead to activation or increased production of another angiogenic molecule, suggesting the absence of a “salvage pathway” that can circumvent or rescue the blockage of bFGF/FGFR-1 in the melanoma cells
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