ABSTRACT
Members of the vascular endothelial growth factor (VEGF) family are crucial regulators of neovascularization and are classified as cystine knot growth factors that specifically bind cellular receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3 with high but variable affinity and selectivity. The VEGF family has recently been expanded and currently comprises seven members: VEGF-A, VEGF-B, placenta growth factor (PlGF), VEGF-C, VEGF-D, viral VEGF (also known as VEGF-E), and snake venom VEGF (also known as VEGF-F). Although all members are structurally homologous, there is molecular diversity among the subtypes, and several isoforms, such as VEGF-A, VEGF-B, and PlGF, are generated by alternative exon splicing. These splicing isoforms exhibit differing properties, particularly in binding to co-receptor neuropilins and heparin. VEGF family proteins play multiple physiological roles, such as angiogenesis and lymphangiogenesis, while exogenous members (viral and snake venom VEGFs) display activities that are unique in physiology and function. This review will highlight the molecular and functional diversity of VEGF family proteins.
Subject(s)
Genetic Variation , Vascular Endothelial Growth Factors/genetics , Vascular Endothelial Growth Factors/physiology , Amino Acid Sequence , Animals , Humans , Models, Biological , Molecular Sequence Data , Protein Binding , Sequence Homology, Amino Acid , Signal Transduction , Snake Venoms/chemistry , Snake Venoms/genetics , Vascular Endothelial Growth Factors/chemistry , Vascular Endothelial Growth Factors/classificationABSTRACT
BACKGROUND: Antigen presenting cells, in particular dendritic cells (DCs), are critical elements in antitumor immunity induction. Some of the angiogenic factors released by tumor and stroma cells, including vascular endothelial growth factor (VEGF), are thought to affect DC function. MATERIAL/METHODS: The expression of Vascular Endothelial Growth Factor (VEGF) isoforms VEGF-A (121, 145,165, 189, 206), VEGF-C and VEGF-D were determined by immunohistochemistry, Western blotting and ELISA in 46 patients with Head and Neck Squamous Cell Carcinoma (HNSCC), 30 healthy donors, and two HNSCC tumor cell lines (PCI-1 and PCI-13). RESULTS: Increased expression of VEGF-A and VEGF-C was found in tumor tissues compared to normal epithelium (P=0.001). However, VEGF-D levels were decreased in patients with cervical nodal metastasis as compared to patients with negative lymph node status. VEGF-A plasma levels were increased in patients with lymph node metastasis (266 pg/ml) compared to patients with negative lymph node status (19.8 pg/ml). Multivariate analysis demonstrated that VEGF-A correlated with microvessel density (P=0.01), disease progression (P=0.038), a reduced number of local and peripheral mature dendritic cells (DC) (P=0.015) and an increased number of peripheral immature DCs (P=0.05). DCs incubated with tumor supernatant or VEGF-A differentiated into immature DCs and did not develop full allostimulatory activity. Allogenic T cells, when co-cultured with these immature DCs, expressed the T regulatory cell marker CD25, CTLA-4, and CD45Ro, and secreted TGF-beta, VEGF-A and IL-10. CONCLUSIONS: Taken together, our results identify VEGF-A as a multifunctional factor involved in angiogenesis, tumor progression, immunosuppression and immune tolerance.
Subject(s)
Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/pathology , Immune Tolerance , Neovascularization, Pathologic , Vascular Endothelial Growth Factors/metabolism , Adult , Aged , Cell Count , Cell Differentiation , Cell Line, Tumor , Cell Movement , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/blood supply , Head and Neck Neoplasms/metabolism , Humans , Macrophages/cytology , Macrophages/immunology , Male , Middle Aged , Mucous Membrane/metabolism , Phenotype , Protein Isoforms/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Vascular Endothelial Growth Factors/blood , Vascular Endothelial Growth Factors/classificationABSTRACT
Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro- and antiangiogenic molecules have already been discovered. Vascular endothelial growth factor (VEGF) is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF in physiological and pathological processes is reviewed. We also discuss how modulation of VEGF expression creates new therapeutic possibilities and describe recent developments in this field.