1. Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene
- Author
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Giuseppe Viglietto, Gaetano Salvatore, Gaetano De Rosa, Alfredo Fusco, M. Graziella Persico, Stefania Staibano, Gustavo Baldassarre, Paola Ferraro, Paola Bruni, Claudio Arra, Barbara Belletti, Belletti, B, Ferraro, P, Arra, C, Baldassarre, G, Bruni, P, Staibano, Stefania, DE ROSA, Gaetano, Salvatore, G, Fusco, Alfredo, Persico, Mg, and Viglietto, G.
- Subjects
Vascular Endothelial Growth Factor A ,Cancer Research ,Angiogenesis ,pathology, Neovascularization ,Endothelial Growth Factors ,Neoplastic, Humans, Lymphokine ,chemistry.chemical_compound ,Mice ,Tumor Cells, Cultured ,Growth factor receptor inhibitor ,Animals, Carcinogenicity Tests, Carcinoma ,Lymphokines ,Neovascularization, Pathologic ,Vascular Endothelial Growth Factors ,Growth Factor ,Nude, Neoplasm ,genetics, Endothelial Growth Factor ,genetics/metabolism/pathology, Tumor Cell ,Vascular endothelial growth factor ,Vascular endothelial growth factor B ,Gene Expression Regulation, Neoplastic ,Vascular endothelial growth factor A ,Vascular endothelial growth factor C ,Vascular Endothelial Growth Factor, Thyroid Neoplasm ,Pathologic, Proto-Oncogene Protein ,Cell Division ,medicine.medical_specialty ,genetics, RNA ,Carcinogenicity Tests ,Mice, Nude ,Biology ,Experimental ,genetics/metabolism/pathology, Cell Division ,Internal medicine ,Proto-Oncogene Proteins ,Genetics ,medicine ,Animals ,Humans ,genetics/metabolism, Gene Expression Regulation ,RNA, Antisense ,Receptors, Growth Factor ,Thyroid Neoplasms ,Antisense ,Molecular Biology ,genetics, Receptor ,Vascular Endothelial Growth Factor Receptor-1 ,genetics, Receptor Protein-Tyrosine Kinase ,Cell growth ,Carcinoma ,Receptor Protein-Tyrosine Kinases ,Neoplasms, Experimental ,Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factors ,Endocrinology ,Receptors, Vascular Endothelial Growth Factor ,chemistry ,Cell culture ,genetics/metabolism, Mice, Mice ,Cancer research - Abstract
Vascular endothelial growth factor A (VEGF) is a potent mitogen for endothelial cells in vitro and promotes neo-angiogenesis in vivo. VEGF overexpression occurs in most human malignancies including thyroid carcinomas in which elevated VEGF expression is associated with a high tumorigenic potential. To investigate the role of VEGF in angiogenesis associated with development of thyroid carcinomas, we constitutively expressed VEGF121 into a poorly tumorigenic cell line (NPA) expressing minimal levels of endogenous VEGF. Here we report that VEGF overexpressing NPA cells showed the same growth potential as untransfected NPA in vitro but formed well-vascularized tumors when injected subcutaneously into nude mice with markedly reduced latency compared to parental cells. A complementary approach was to suppress VEGF expression in a highly tumorigenic anaplastic cell line (ARO) by the transfection of an antisense construct. Antisense-transfected ARO cells expressed reduced constitutive levels of VEGF, showed the same growth potential as untransfected ARO cells in vitro and formed small tumors characterized by minimal vascularization, extensive necrosis and longer latency compared to parental or vector-transfected ARO cells in vivo. Finally, we investigated the expression of both VEGF tyrosine kinase receptors (Flt-1 and Flk-1/KDR) in tumor specimens by RT - PCR. Expression of (Flt-1 and Flk-1/KDR) was low in tissue specimens derived from NPA tumors, but was found enhanced in NPA VEGF tumors; conversely, the expression of VEGF receptors was high in tissue specimens derived from ARO tumors but was decreased in tumors derived from VEGF depleted ARO cells. These results clearly demonstrate that VEGF indirectly promotes the growth of thyroid tumors by stimulating angiogenesis.
- Published
- 1999