Abstract
Angiogenesis is required for the progression of tumors from a benign to a malignant phenotype and for metastasis. Malignant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Here it is shown that several tumor types express VEGF receptors (VEGFRs) and that inhibition of VEGF (VEGF antisense oligonucleotide AS-3) or VEGFRs (neutralizing antibodies) inhibited the proliferation of these cell lines in vitro. Furthermore, this effect was abrogated by exogenous VEGF. Thus, VEGF is an autocrine growth factor for tumor cell lines that express VEGFRs. A modified form of VEGF AS-3 (AS-3m), in which flanking 4 nucleotides were substituted with 2-O-methylnucleosides (mixed backbone oligonucleotides), retained specificity and was active when given orally or systemically in vitro and in murine tumor models. In VEGFR-2-expressing tumors, VEGF inhibition may have dual functions: direct inhibition of tumor cell growth and inhibition of angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies / pharmacology
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Autocrine Communication
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Cell Division / drug effects
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / physiology*
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Humans
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Lymphokines / physiology*
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Male
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Mice
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Mice, Inbred BALB C
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Neoplasms / blood supply
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Neoplasms / pathology*
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Neovascularization, Pathologic
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Oligonucleotides
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Oligonucleotides, Antisense / pharmacology
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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RNA, Neoplasm / biosynthesis
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Receptor Protein-Tyrosine Kinases / biosynthesis*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / immunology
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Receptors, Growth Factor / biosynthesis*
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Receptors, Growth Factor / genetics
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Receptors, Growth Factor / immunology
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Receptors, Vascular Endothelial Growth Factor
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
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Xenograft Model Antitumor Assays
Substances
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AS-3m oligonucleotide
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Antibodies
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Endothelial Growth Factors
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Lymphokines
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Oligonucleotides
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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RNA, Neoplasm
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1