THE ROLE OF VEGF FAMILY IN ANGIOGENESIS, TUMOR GROWTH AND METASTASIS

摘要: Tumor growth is dependent on angiogenesis, and cells in tumor tissues produce various angiogenic factors to induce neovascularization. Among tumor-derived factors, members of the vascular endothelial factor (VEGF) family are most frequently and highly expressed solid tumors. VEGF-A, prototype VEGF, most powerful pro-angiogenic that binds VEGF receptor-1 (VEGFR-1, also called FMSRelated Tyrosine Kinase-1/Flt-1) VEGFR-2 (also Kinase Insert Domain Receptor/KDR or Fetal Liver -1/Flk-1). While VEGFR-2-transduced angiogenic signals, pathways, functions well characterized, VEGFR-1-mediated are poorly understood. The placental (PlGF), which a specific VEGFR-1-binding ligand, remain controversial. role VEGF-B tumor angiogenesis still unclear. In addition, two other members, VEGF-C and VEGF-D major lymphangiogenic contribute lymphatic metastasis. The work contained this thesis aimed study members in angiogenesis, metastasis. Our shows PlGF exhibits a duality in modulation angiogenesis VEGF-A-dependent manner. This noted when cell-derived sensitizes anti-angiogenic anti-tumor effects anti-VEGF drugs. We noted treatment induces various vascular alterations mouse healthy tissues. Additionally, we revealed collaborative interaction between FGF-2 promotion lymphangiogenesis metastasis. In paper I, using independent models, show modulated growth, angiogenesis, remodeling through VEGF-dependent mechanism either a positive negative VEGF-A positive model, inhibited growth and leading normalized vasculature with dilated vessel lumens, infrequent branches increased perivascular cell coverage. Surprisingly, the VEGF-A overexpression resulted opposite phenotype that seen namely accelerated rates abundant chaotic vessels. data uncovered molecular mechanisms underlying the complex interplay VEGF-A. These findings have conceptual implications for cancer therapy. In II, tumors from humans mice high levels expression of PlGF were hypersensitive anti-VEGF-A anti-VEGFR-2 therapies. then validated this finding loss-of-function experiment PLGF shRNA human choriocarcinoma line. Down-regulation significantly growth rate led resistance VEGFR-1 neutralizing antibodies displayed opposing effects angiogenesis. These findings demonstrate negatively modulates and sensitizes effect drugs tumors, level in VEGF-A may potentially be predictive marker therapy. In III, investigated alteration organs after systemic treatment with anti-VEGF-A, anti-VEGFR-1 neutralizing antibodies. study provides functional structural for drug-induced adverse in patients. In IV, looked into fibroblast factor-2 (FGF-2) on angiogenesis, results showed and VEGF-C could both separately collaboratively promote and lymphangiogenesis cornea tissue, resulting in pulmonary lymph node metastases animal models. By blocking VEGFR-3 FGF receptor-1 (FGFR-1), fact VEGFR-3-induced endothelial cell (LEC) tip formation necessity FGF-2-FGFR-1 signaling stimulated lymphangiogenesis. suggests combined targeting VEGF-C might an effective approach therapy prevention