Vascular endothelial growth factor (VEGF) signaling in tumor progression

Critical Reviews in Oncology/Hematology - Tập 62 - Trang 179-213 - 2007
Robert Roskoski1
1Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116A, Box 19, Horse Shoe, NC 28742, USA

Tài liệu tham khảo

Cines, 1998, Endothelial cells in physiology and in the pathophysiology of vascular disorders, Blood, 91, 3527 Dvorak, 2005, Angiogenesis: update 2005, J Thromb Haemost, 3, 1835, 10.1111/j.1538-7836.2005.01361.x Coultas, 2005, Endothelial cells and VEGF in vascular development, Nature, 438, 937, 10.1038/nature04479 Aghi, 2005, Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors, Mol Ther, 12, 994, 10.1016/j.ymthe.2005.07.693 Asahara, 1997, Isolation of putative progenitor endothelial cells for angiogenesis, Science, 275, 964, 10.1126/science.275.5302.964 Zammaretti, 2005, Adult ‘endothelial progenitor cells’. Renewing vasculature, Int J Biochem Cell Biol, 37, 493, 10.1016/j.biocel.2004.06.018 Ziegelhoeffer, 2004, Bone marrow-derived cells do not incorporate into the adult growing vasculature, Circ Res, 94, 230, 10.1161/01.RES.0000110419.50982.1C Folkman, 2006, Tumor angiogenesis, 157 Hanahan, 1996, Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis, Cell, 86, 353, 10.1016/S0092-8674(00)80108-7 Ferrara, 2004, Vascular endothelial growth factor: basic science and clinical progress, Endocr Rev, 25, 581, 10.1210/er.2003-0027 Eklund, 2006, Tie receptors and their angiopoietin ligands are context-dependent regulators of vascular remodeling, Exp Cell Res, 312, 630, 10.1016/j.yexcr.2005.09.002 Heroult, 2006, Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression, Exp Cell Res, 312, 642, 10.1016/j.yexcr.2005.10.028 Relf, 1997, Cancer Res, 57, 963 Nyberg, 2005, Endogenous inhibitors of angiogenesis, Cancer Res, 65, 3967, 10.1158/0008-5472.CAN-04-2427 O’Reilly, 1994, Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma, Cell, 79, 315, 10.1016/0092-8674(94)90200-3 O’Reilly, 1997, Endostatin: an endogenous inhibitor of angiogenesis and tumor growth, Cell, 88, 277, 10.1016/S0092-8674(00)81848-6 Dameron, 1994, Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1, Science, 265, 1582, 10.1126/science.7521539 Pepper, 1997, Manipulating angiogenesis. From basic science to the bedside, Arterioscler Thromb Vasc Biol, 17, 605, 10.1161/01.ATV.17.4.605 Auguste, 2005, Molecular mechanisms of tumor vascularization, Crit Rev Oncol Hematol, 54, 53, 10.1016/j.critrevonc.2004.11.006 Patan, 1996, Intussusceptive microvascular growth in a human colon adenocarcinoma xenograft: a novel mechanism of tumor angiogenesis, Microvasc Res, 51, 260, 10.1006/mvre.1996.0025 Holash, 1999, Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF, Science, 284, 1994, 10.1126/science.284.5422.1994 Chang, 2000, Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood, Proc Natl Acad Sci USA, 97, 14608, 10.1073/pnas.97.26.14608 Maniotis, 1999, Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry, Am J Pathol, 155, 739, 10.1016/S0002-9440(10)65173-5 Hendrix, 2003, Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma, Nat Rev Cancer, 3, 411, 10.1038/nrc1092 Less, 1991, Microvascular architecture in a mammary carcinoma: branching patterns and vessel dimensions, Cancer Res, 51, 265 Algire, 1945, Vascular reactions of normal and malignant tissues in vivo. I. Vascular reactions of mice to wounds and to normal and neoplastic transplants, J Natl Cancer Inst, 6, 73, 10.1093/jnci/6.1.73 Jain, 2003, Molecular regulation of vessel maturation, Nature Med, 9, 685, 10.1038/nm0603-685 Gerwins, 2000, Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis, Crit Rev Oncol Hematol, 34, 185, 10.1016/S1040-8428(00)00062-7 Hoeben, 2004, Vascular endothelial growth factor and angiogenesis, Pharmacol Rev, 56, 549, 10.1124/pr.56.4.3 Robinson, 2001, The splice variants of vascular endothelial growth factor (VEGF) and their receptors, J Cell Sci, 114, 853, 10.1242/jcs.114.5.853 Kärpänen, 2006, Functional interaction of VEGF-C and VEGF-D with neuropilin receptors, FASEB J, 20, 1462, 10.1096/fj.05-5646com Plöuet, 1990, Characterization of the receptors for vasculotropin on bovine adrenal cortex-derived capillary endothelial cells, J Biol Chem, 265, 22071, 10.1016/S0021-9258(18)45668-2 Vaisman, 1990, Characterization of the receptors for vascular endothelial growth factor, J Biol Chem, 265, 19461, 10.1016/S0021-9258(17)45395-6 Shibuya, 1990, Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family, Oncogene, 5, 519 Matthews, 1991, A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit, Proc Natl Acad Sci USA, 88, 9026, 10.1073/pnas.88.20.9026 Terman, 1991, Identification of a new endothelial cell growth factor receptor tyrosine kinase, Oncogene, 6, 1677 Terman, 1992, Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor, Biochem Biophys Res Commun, 187, 1579, 10.1016/0006-291X(92)90483-2 Pajusola, 1992, FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines, Cancer Res, 52, 5738 Fantl, 1993, Signalling by receptor tyrosine kinases, Annu Rev Biochem, 62, 453, 10.1146/annurev.bi.62.070193.002321 Hubbard, 2000, Protein tyrosine kinase structure and function, Annu Rev Biochem, 69, 373, 10.1146/annurev.biochem.69.1.373 Senger, 1983, Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid, Science, 219, 983, 10.1126/science.6823562 Ferrara, 1989, Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells, Biochem Biophys Res Commun, 161, 851, 10.1016/0006-291X(89)92678-8 Gospodarowicz, 1989, Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells, Proc Natl Acad Sci USA, 86, 7311, 10.1073/pnas.86.19.7311 Connolly, 1989, Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis, J Clin Invest, 84, 1470, 10.1172/JCI114322 Senger, 1990, Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor, Cancer Res, 50, 1774 Plouët, 1989, Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells, EMBO J, 8, 3801, 10.1002/j.1460-2075.1989.tb08557.x Levy, 1989, An endothelial cell growth factor from the mouse neuroblastoma cell line NB41, Growth Factors, 2, 9, 10.3109/08977198909069077 Leung, 1989, Vascular endothelial growth factor is a secreted angiogenic mitogen, Science, 246, 1306, 10.1126/science.2479986 Keck, 1989, Vascular permeability factor, an endothelial cell mitogen related to PDGF, Science, 246, 1309, 10.1126/science.2479987 Conn, 1990, Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor, Proc Natl Acad Sci USA, 87, 2628, 10.1073/pnas.87.7.2628 Alon, 1995, Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity, Nat Med, 1, 1024, 10.1038/nm1095-1024 Gerber, 1998, Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation, J Biol Chem, 273, 30336, 10.1074/jbc.273.46.30336 Waltenberger, 1994, Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor, J Biol Chem, 269, 26988, 10.1016/S0021-9258(18)47116-5 Clauss, 1990, Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration, J Exp Med, 172, 1535, 10.1084/jem.172.6.1535 Barleon, 1996, Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1, Blood, 87, 3336, 10.1182/blood.V87.8.3336.bloodjournal8783336 Tischer, 1991, The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing, J Biol Chem, 266, 11947, 10.1016/S0021-9258(18)99049-6 Guttmann-Raviv, 2006, The neuropilins and their role in tumorigenesis and tumor progression, Cancer Lett, 231, 1, 10.1016/j.canlet.2004.12.047 Berse, 1992, Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors, Mol Biol Cell, 3, 211, 10.1091/mbc.3.2.211 Breier, 1992, Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation, Development, 114, 521, 10.1242/dev.114.2.521 Ng, 2001, Differential expression of VEGF isoforms in mouse during development and in the adult, Dev Dyn, 220, 112, 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1093>3.0.CO;2-D Maharaj, 2006, Vascular endothelial growth factor localization in the adult, Am J Pathol, 168, 639, 10.2353/ajpath.2006.050834 Carmeliet, 1996, Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele, Nature, 380, 435, 10.1038/380435a0 Ferrara, 1996, Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene, Nature, 380, 439, 10.1038/380439a0 Muller, 1997, Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site, Proc Natl Acad Sci USA, 94, 7192, 10.1073/pnas.94.14.7192 Olofsson, 1996, Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform, J Biol Chem, 271, 19310, 10.1074/jbc.271.32.19310 Iyer, 2006, Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding, J Mol Biol, 359, 76, 10.1016/j.jmb.2006.03.002 Lagercrantz, 1998, A comparative study of the expression patterns for vegf, vegf-b/vrf and vegf-c in the developing and adult mouse, Biochim Biophys Acta, 1398, 157, 10.1016/S0167-4781(98)00040-2 Salven, 1998, Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors, Am J Pathol, 153, 103, 10.1016/S0002-9440(10)65550-2 Tammela, 2005, The biology of vascular endothelial growth factors, Cardiovasc Res, 65, 550, 10.1016/j.cardiores.2004.12.002 Aase, 2001, Vascular endothelial growth factor-B-deficient mice display an atrial conduction defect, Circulation, 104, 358, 10.1161/01.CIR.104.3.358 Joukov, 1996, A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases, EMBO J, 15, 1751, 10.1002/j.1460-2075.1996.tb00521.x Joukov, 1997, Proteolytic processing regulates receptor specificity and activity of VEGF-C, EMBO J, 16, 3898, 10.1093/emboj/16.13.3898 Zhou, 1999, Proteolytic processing in the secretory pathway, J Biol Chem, 274, 20745, 10.1074/jbc.274.30.20745 Siegfried, 2003, The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis, J Clin Invest, 111, 1723, 10.1172/JCI200317220 Chilov, 1997, Genomic organization of human and mouse genes for vascular endothelial growth factor C, J Biol Chem, 272, 25176, 10.1074/jbc.272.40.25176 Kukk, 1996, VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development, Development, 122, 3829, 10.1242/dev.122.12.3829 Lymboussaki, 1999, Vascular endothelial growth factor (VEGF) and VEGF-C show overlapping binding sites in embryonic endothelia and distinct sites in differentiated adult endothelia, Circ Res, 85, 992, 10.1161/01.RES.85.11.992 Su, 2006, The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells, Cancer Cell, 9, 209, 10.1016/j.ccr.2006.02.018 Shida, 2006, Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma, Int J Clin Oncol, 11, 38, 10.1007/s10147-005-0528-3 Karkkainen, 2004, Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins, Nat Immunol, 5, 74, 10.1038/ni1013 Stacker, 1999, Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers, J Biol Chem, 274, 32127, 10.1074/jbc.274.45.32127 Yamada, 1997, Molecular cloning of a novel vascular endothelial growth factor, VEGF-D, Genomics, 42, 483, 10.1006/geno.1997.4774 Rocchigiani, 1998, Human FIGF: cloning, gene structure, and mapping to chromosome Xp22.1 between the PIGA and the GRPR genes, Genomics, 47, 207, 10.1006/geno.1997.5079 Baldwin, 2005, Vascular endothelial growth factor D is dispensable for development of the lymphatic system, Mol Cell Biol, 25, 2441, 10.1128/MCB.25.6.2441-2449.2005 Achen, 1998, Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4), Proc Natl Acad Sci USA, 95, 548, 10.1073/pnas.95.2.548 Nakamura, 2003, Prognostic significance of vascular endothelial growth factor D in breast carcinoma with long-term follow-up, Clin Cancer Res, 9, 716 White, 2002, Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma, Cancer Res, 62, 1669 Yasuoka, 2005, VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma, Mod Pathol, 18, 1127, 10.1038/modpathol.3800402 Van Trappen, 2003, Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis, J Pathol, 201, 544, 10.1002/path.1467 Debinski, 2001, VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme, Mol Med, 7, 598, 10.1007/BF03401866 Achen, 2001, Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis, J Pathol, 193, 147, 10.1002/1096-9896(2000)9999:9999<::AID-PATH757>3.0.CO;2-G Funaki, 2003, Expression of vascular endothelial growth factor D is associated with lymph node metastasis in human colorectal carcinoma, Oncology, 64, 416, 10.1159/000070301 Niki, 2000, Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma, Clin Cancer Res, 6, 2431 Yokoyama, 2003, Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma, Br J Cancer, 88, 237, 10.1038/sj.bjc.6600701 Maglione, 1991, Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor, Proc Natl Acad Sci USA, 88, 9267, 10.1073/pnas.88.20.9267 Iyer, 2001, The crystal structure of human placenta growth factor-1 (PlGF-1), an angiogenic protein, at 2.0Å resolution, J Biol Chem, 276, 12153, 10.1074/jbc.M008055200 Maglione, 1993, Two alternative mRNAs coding for the angiogenic factor, placenta growth factor (PlGF), are transcribed from a single gene of chromosome 14, Oncogene, 8, 925 Cao, 1997, Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing, Biochem Biophys Res Commun, 235, 493, 10.1006/bbrc.1997.6813 Yang, 2003, Evidence of a novel isoform of placenta growth factor (PlGF-4) expressed in human trophoblast and endothelial cells, J Reprod Immunol, 60, 53, 10.1016/S0165-0378(03)00082-2 Parr, 2005, Placenta growth factor is over-expressed and has prognostic value in human breast cancer, Eur J Cancer, 41, 2819, 10.1016/j.ejca.2005.07.022 Chen, 2004, The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer, Cancer Lett, 213, 73, 10.1016/j.canlet.2004.05.020 Matsumoto, 2003, Placental growth factor gene expression in human prostate cancer and benign prostate hyperplasia, Anticancer Res, 23, 3767 Zhang, 2005, Expression of placenta growth factor (PlGF) in non-small cell lung cancer (NSCLC) and the clinical and prognostic significance, World J Surg Oncol, 3, 68, 10.1186/1477-7819-3-68 Iwama, 2006, Cardiac expression of placental growth factor predicts the improvement of chronic phase left ventricular function in patients with acute myocardial infarction, J Am Coll Cardiol, 47, 1559, 10.1016/j.jacc.2005.11.064 Persico, 1999, Structure, expression and receptor-binding properties of placenta growth factor (PlGF), Curr Top Microbiol Immunol, 237, 31, 10.1007/978-3-642-59953-8_2 Feeney, 2003, Role of vascular endothelial growth factor and placental growth factors during retinal vascular development and hyaloid regression, Invest Ophthalmol Vis Sci, 44, 839, 10.1167/iovs.02-0040 Failla, 2000, Placenta growth factor is induced in human keratinocytes during wound healing, J Invest Dermatol, 115, 388, 10.1046/j.1523-1747.2000.00085.x Odorisio, 2006, The placenta growth factor in skin angiogenesis, J Dermatol Sci, 41, 11, 10.1016/j.jdermsci.2005.08.008 Carmeliet, 2001, Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions, Nat Med, 7, 575, 10.1038/87904 Meyer, 1999, A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signaling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases, EMBO J, 18, 363, 10.1093/emboj/18.2.363 Park, 1994, Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR, J Biol Chem, 269, 25646, 10.1016/S0021-9258(18)47298-5 Olofsson, 1998, Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells, Proc Natl Acad Sci USA, 95, 11709, 10.1073/pnas.95.20.11709 de Vries, 1992, The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor, Science, 255, 989, 10.1126/science.1312256 Peters, 1993, Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth, Proc Natl Acad Sci USA, 90, 8915, 10.1073/pnas.90.19.8915 Quinn, 1993, Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium, Proc Natl Acad Sci USA, 90, 7533, 10.1073/pnas.90.16.7533 Kendall, 1993, Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor, Proc Natl Acad Sci USA, 90, 10705, 10.1073/pnas.90.22.10705 Clark, 1998, A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation, Biol Reprod, 59, 1540, 10.1095/biolreprod59.6.1540 Robinson, 2006, Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia, Am J Obstet Gynecol, 195, 255, 10.1016/j.ajog.2005.12.049 Ito, 1998, Identification of vascular endothelial growth factor receptor-1 tyrosine phosphorylation sites and binding of SH2 domain-containing molecules, J Biol Chem, 273, 23410, 10.1074/jbc.273.36.23410 Sawano, 1997, The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCγ, Biochem Biophys Res Commun, 238, 487, 10.1006/bbrc.1997.7327 Olsson, 2006, VEGF receptor signalling—in control of vascular function, Nat Rev Mol Cell Biol, 7, 359, 10.1038/nrm1911 Autiero, 2003, Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1, Nat Med, 9, 936, 10.1038/nm884 Wiesmann, 1997, Crystal structure at 1.7Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor, Cell, 91, 695, 10.1016/S0092-8674(00)80456-0 Christinger, 2004, The crystal structure of placental growth factor in complex with domain 2 of vascular endothelial growth factor receptor-1, J Biol Chem, 279, 10382, 10.1074/jbc.M313237200 Gille, 2001, Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2), J Biol Chem, 276, 3222, 10.1074/jbc.M002016200 Takahashi, 2001, A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A—dependent activation of PLC-γ and DNA synthesis in vascular endothelial cells, EMBO J, 20, 2768, 10.1093/emboj/20.11.2768 Bernatchez, 1999, Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent, J Biol Chem, 274, 31047, 10.1074/jbc.274.43.31047 Matsumoto, 2005, VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis, EMBO J, 24, 2342, 10.1038/sj.emboj.7600709 Shibuya, 2006, Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis, Exp Cell Res, 312, 549, 10.1016/j.yexcr.2005.11.012 Kendall, 1999, Vascular endothelial growth factor receptor KDR tyrosine kinase activity is increased by autophosphorylation of two activation loop tyrosine residues, J Biol Chem, 274, 6453, 10.1074/jbc.274.10.6453 Holmqvist, 2004, The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration, J Biol Chem, 279, 22267, 10.1074/jbc.M312729200 Ebos, 2004, A naturally occurring soluble form of vascular endothelial growth factor receptor 2 detected in mouse and human plasma, Mol Cancer Res, 2, 315, 10.1158/1541-7786.315.2.6 Gerber, 1997, Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia, J Biol Chem, 272, 23659, 10.1074/jbc.272.38.23659 Pajusola, 1992, FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines, Cancer Res, 52, 5738 Galland, 1993, The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor, Oncogene, 8, 1233 Kaipainen, 1995, Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development, Proc Natl Acad Sci USA, 92, 3566, 10.1073/pnas.92.8.3566 Nilsson, 2004, Vascular endothelial growth factor receptor-3 in hypoxia-induced vascular development, FASEB J, 18, 1507, 10.1096/fj.03-1276com Dixelius, 2003, Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites, J Biol Chem, 278, 40973, 10.1074/jbc.M304499200 Alam, 2004, Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity, Biochem Biophys Res Commun, 324, 909, 10.1016/j.bbrc.2004.08.237 Soker, 1998, Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor, Cell, 92, 735, 10.1016/S0092-8674(00)81402-6 Takagi, 1991, The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors, Neuron, 7, 295, 10.1016/0896-6273(91)90268-5 Takagi, 1995, Expression of a cell adhesion molecule, neuropilin, in the developing chick nervous system, Dev Biol, 170, 207, 10.1006/dbio.1995.1208 Chen, 2000, Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections, Neuron, 25, 43, 10.1016/S0896-6273(00)80870-3 Bielenberg, 2006, Neuropilins in neoplasms: expression, regulation, and function, Exp Cell Res, 312, 584, 10.1016/j.yexcr.2005.11.024 Ellis, 2006, The role of neuropilins in cancer, Mol Cancer Ther, 5, 1099, 10.1158/1535-7163.MCT-05-0538 1999, Unified nomenclature for the semaphorins/collapsins, Cell, 97, 551, 10.1016/S0092-8674(00)80766-7 Neufeld, 2002, The interaction of neuropilin-1 and neuropilin-2 with tyrosine-kinase receptors for VEGF, Adv Exp Med Biol, 515, 81, 10.1007/978-1-4615-0119-0_7 Migdal, 1998, Neuropilin-1 is a placenta growth factor-2 receptor, J Biol Chem, 273, 22272, 10.1074/jbc.273.35.22272 Makinen, 1999, Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1, J Biol Chem, 274, 21217, 10.1074/jbc.274.30.21217 Gluzman-Poltorak, 2000, Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165, J Biol Chem, 275, 18040, 10.1074/jbc.M909259199 Karkkainen, 2001, A model for gene therapy of human hereditary lymphedema, Proc Natl Acad Sci USA, 98, 12677, 10.1073/pnas.221449198 Mamluk, 2002, Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain, J Biol Chem, 277, 24818, 10.1074/jbc.M200730200 Takahashi, 1998, Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors, Nat Neurosci, 1, 487, 10.1038/2203 Favier, 2006, Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration, Blood, 108, 1243, 10.1182/blood-2005-11-4447 Ding, 2000, Expression and regulation of neuropilin-1 in human astrocytomas, Int J Cancer, 88, 584, 10.1002/1097-0215(20001115)88:4<584::AID-IJC11>3.0.CO;2-T Sanchez-Carbayo, 2003, Gene discovery in bladder cancer progression using cDNA microarrays, Am J Pathol, 163, 505, 10.1016/S0002-9440(10)63679-6 Ochiumi, 2006, Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer, Int J Oncol, 29, 105 Hansel, 2004, Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract, Am J Surg Pathol, 28, 347, 10.1097/00000478-200403000-00007 Rieger, 2003, Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins, Glia, 42, 379, 10.1002/glia.10210 Lacal, 2000, Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor, J Invest Dermatol, 115, 1000, 10.1046/j.1523-1747.2000.00199.x Beierle, 2003, VEGF receptors are differentially expressed by neuroblastoma cells in culture, J Pediatr Surg, 38, 514, 10.1053/jpsu.2003.50091 Lantuejoul, 2003, Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines, J Pathol, 200, 336, 10.1002/path.1367 Parikh, 2003, Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth factor in human pancreatic carcinoma, Cancer, 98, 720, 10.1002/cncr.11560 Fukahi, 2004, Aberrant expression of neuropilin-1 and -2 in human pancreatic cancer cells, Clin Cancer Res, 10, 581, 10.1158/1078-0432.CCR-0930-03 Miao, 2000, Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression, FASEB J, 14, 2532, 10.1096/fj.00-0250com Latil, 2000, VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms, Int J Cancer, 89, 167, 10.1002/(SICI)1097-0215(20000320)89:2<167::AID-IJC11>3.0.CO;2-9 Akagi, 2003, Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells, Br J Cancer, 88, 796, 10.1038/sj.bjc.6600811 Parikh, 2004, Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis, Am J Pathol, 164, 2139, 10.1016/S0002-9440(10)63772-8 Wey, 2005, Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells, Br J Cancer, 93, 233, 10.1038/sj.bjc.6602663 Shi, 2001, Pancreatic cancer: factors regulating tumor development, maintenance and metastasis, Pancreatology, 1, 517, 10.1159/000055854 Barr, 2005, A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells, Br J Cancer, 92, 328, 10.1038/sj.bjc.6602308 Castro-Rivera, 2004, Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect, Proc Natl Acad Sci USA, 101, 11432, 10.1073/pnas.0403969101 Nasarre, 2003, Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading, Neoplasia, 5, 83, 10.1016/S1476-5586(03)80020-9 Nasarre, 2005, Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion, Neoplasia, 7, 180, 10.1593/neo.04481 Roche, 1996, Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin, Oncogene, 12, 1289 Sekido, 1996, Human semaphorins A (V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns, Proc Natl Acad Sci USA, 93, 4120, 10.1073/pnas.93.9.4120 Xiang, 1996, Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer, Genomics, 32, 39, 10.1006/geno.1996.0074 Kusy, 2005, Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells, Neoplasia, 7, 457, 10.1593/neo.04721 Kessler, 2004, Semaphorin-3F is an inhibitor of tumor angiogenesis, Cancer Res, 64, 1008, 10.1158/0008-5472.CAN-03-3090 Gagnon, 2000, Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity, Proc Natl Acad Sci USA, 97, 2573, 10.1073/pnas.040337597 Oh, 2002, Selective induction of neuropilin-1 by vascular endothelial growth factor (VEGF): a mechanism contributing to VEGF-induced angiogenesis, Proc Natl Acad Sci USA, 99, 383, 10.1073/pnas.012074399 Ottino, 2004, Hypoxia activates matrix metalloproteinase expression and the VEGF system in monkey choroid-retinal endothelial cells: Involvement of cytosolic phospholipase A2 activity, Mol Vis, 10, 341 Fujita, 2001, Expressions of neuropilin-1, neuropilin-2 and semaphorin 3A mRNA in the rat brain after middle cerebral artery occlusion, Brain Res, 914, 1, 10.1016/S0006-8993(01)02765-2 Fong, 1995, Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium, Nature, 376, 66, 10.1038/376066a0 Hiratsuka, 1998, Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice, Proc Natl Acad Sci USA, 95, 9349, 10.1073/pnas.95.16.9349 Shalaby, 1995, Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice, Nature, 376, 62, 10.1038/376062a0 Dumont, 1998, Cardiovascular failure in mouse embryos deficient in VEGF receptor-3, Science, 282, 946, 10.1126/science.282.5390.946 Kawasaki, 1999, A requirement for neuropilin-1 in embryonic vessel formation, Development, 126, 4895, 10.1242/dev.126.21.4895 Kitsukawa, 1995, Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs, Development, 121, 4309, 10.1242/dev.121.12.4309 Kitsukawa, 1997, Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice, Neuron, 19, 995, 10.1016/S0896-6273(00)80392-X Chen, 1997, Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III, Neuron, 19, 547, 10.1016/S0896-6273(00)80371-2 Giger, 2000, Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins, Neuron, 25, 29, 10.1016/S0896-6273(00)80869-7 Yuan, 2002, Abnormal lymphatic vessel development in neuropilin 2 mutant mice, Development, 129, 4797, 10.1242/dev.129.20.4797 Takashima, 2002, Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis, Proc Natl Acad Sci USA, 99, 3657, 10.1073/pnas.022017899 Houck, 1992, Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms, J Biol Chem, 267, 26031, 10.1016/S0021-9258(18)35712-0 Flaumenhaft, 1992, The extracellular regulation of growth factor action, Mol Biol Cell, 3, 1057, 10.1091/mbc.3.10.1057 Mignatti, 1993, Biology and biochemistry of proteinases in tumor invasion, Physiol Rev, 73, 161, 10.1152/physrev.1993.73.1.161 Pepper, 2001, Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis, Arterioscler Thromb Vasc Biol, 21, 1104, 10.1161/hq0701.093685 Duffy, 2004, The urokinase plasminogen activator system: role in malignancy, Curr Pharm Des, 10, 39, 10.2174/1381612043453559 Overall, 2006, Tumour microenvironment—opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy, Nat Rev Cancer, 6, 227, 10.1038/nrc1821 Roy, 2006, Making the cut: protease-mediated regulation of angiogenesis, Exp Cell Res, 312, 608, 10.1016/j.yexcr.2005.11.022 Greene, 1996, Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4, J Biol Chem, 271, 30375, 10.1074/jbc.271.48.30375 Keyt, 1996, The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency, J Biol Chem, 271, 7788, 10.1074/jbc.271.13.7788 Whitaker, 2001, Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF(165) and VEGF(121), J Biol Chem, 276, 25520, 10.1074/jbc.M102315200 Lauer, 2000, Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds, J Invest Dermatol, 115, 12, 10.1046/j.1523-1747.2000.00036.x Roth, 2006, Plasmin modulates vascular endothelial growth factor-A-mediated angiogenesis during wound repair, Am J Pathol, 168, 670, 10.2353/ajpath.2006.050372 Plouët, 1997, Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect, J Biol Chem, 272, 13390, 10.1074/jbc.272.20.13390 Lee, 2005, Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors, J Cell Biol, 169, 681, 10.1083/jcb.200409115 Ashikari-Hada, 2005, Heparin regulates vascular endothelial growth factor165-dependent mitogenic activity, tube formation, and its receptor phosphorylation of human endothelial cells. Comparison of the effects of heparin and modified heparins, J Biol Chem, 280, 31508, 10.1074/jbc.M414581200 Carmeliet, 1999, Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188, Nat Med, 5, 495, 10.1038/8379 Stalmans, 2002, Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms, J Clin Invest, 109, 327, 10.1172/JCI0214362 Carmeliet, 2003, Blood vessels and nerves: common signals, pathways and diseases, Nat Rev Genet, 4, 710, 10.1038/nrg1158 Manalo, 2005, Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1, Blood, 105, 659, 10.1182/blood-2004-07-2958 Hirota, 2006, Regulation of angiogenesis by hypoxia-inducible factor 1, Crit Rev Oncol Hematol, 59, 15, 10.1016/j.critrevonc.2005.12.003 Zhou, 2006, Tumor hypoxia and cancer progression, Cancer Lett, 237, 10, 10.1016/j.canlet.2005.05.028 Berra, 2006, The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling, EMBO Rep, 7, 41, 10.1038/sj.embor.7400598 Maxwell, 1999, The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis, Nature, 399, 271, 10.1038/20459 Berra, 2001, HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1α degradation, FEBS Lett, 491, 85, 10.1016/S0014-5793(01)02159-7 Berra, 2003, HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia, EMBO J, 22, 4082, 10.1093/emboj/cdg392 Takeda, 2006, Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2, Mol Cell Biol, 26, 8336, 10.1128/MCB.00425-06 Koivunen, 2004, Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases, J Biol Chem, 279, 9899, 10.1074/jbc.M312254200 Sendroy, 1934, Studies of gas and electrolyte equilibria in blood. XIX. The solubility and physical state of uncombined oxygen in blood, J Biol Chem, 105, 597, 10.1016/S0021-9258(18)75529-4 Forsythe, 1996, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Mol Cell Biol, 16, 4604, 10.1128/MCB.16.9.4604 Goldman, 1993, Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology, Mol Biol Cell, 4, 121, 10.1091/mbc.4.1.121 Ongusaha, 2004, HB-EGF is a potent inducer of tumor growth and angiogenesis, Cancer Res, 64, 5283, 10.1158/0008-5472.CAN-04-0925 Finkenzeller, 1992, Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C, Cancer Res, 52, 4821 Pertovaara, 1994, Vascular endothelial growth factor is induced in response to transforming growth factor-β in fibroblastic and epithelial cells, J Biol Chem, 269, 6271, 10.1016/S0021-9258(17)37365-9 Benckert, 2003, Transforming growth factor β1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells, Cancer Res, 63, 1083 Sugano, 2003, Distortion of autocrine transforming growth factor β signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells, Oncogene, 22, 2309, 10.1038/sj.onc.1206305 Wagner, 2004, Activin A stimulates vascular endothelial growth factor gene transcription in human hepatocellular carcinoma cells, Gastroenterology, 126, 1828, 10.1053/j.gastro.2004.03.011 Ryuto, 1996, Induction of vascular endothelial growth factor by tumor necrosis factor α in human glioma cells. Possible roles of SP-1, J Biol Chem, 271, 28220, 10.1074/jbc.271.45.28220 Kawaguchi, 2004, Regulation of vascular endothelial growth factor expression in human gastric cancer cells by interleukin-1β, Surgery, 136, 686, 10.1016/j.surg.2003.12.015 Cohen, 1996, Interleukin 6 induces the expression of vascular endothelial growth factor, J Biol Chem, 271, 736, 10.1074/jbc.271.2.736 Huang, 2004, Interleukin-6 increases vascular endothelial growth factor and angiogenesis in gastric carcinoma, J Biomed Sci, 11, 517, 10.1007/BF02256101 Bermont, 2001, Insulin up-regulates vascular endothelial growth factor and stabilizes its messengers in endometrial adenocarcinoma cells, J Clin Endocrinol Metab, 86, 363, 10.1210/jc.86.1.363 Warren, 1996, Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma, J Biol Chem, 271, 29483, 10.1074/jbc.271.46.29483 Wang, 2002, VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors, Int J Cancer, 97, 163, 10.1002/ijc.1593 Haggstrom, 1999, Testosterone induces vascular endothelial growth factor synthesis in the ventral prostate in castrated rats, J Urol, 161, 1620, 10.1016/S0022-5347(05)68994-X Lissbrant, 2004, Neutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt(1–3) IgG inhibits testosterone-stimulated prostate growth in castrated mice, Prostate, 58, 57, 10.1002/pros.10312 Hyder, 1998, Progestin regulation of vascular endothelial growth factor in human breast cancer cells, Cancer Res, 58, 392 Liang, 2005, p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells, J Steroid Biochem Mol Biol, 93, 173, 10.1016/j.jsbmb.2004.12.011 Sherr, 2004, Principles of tumor suppression, Cell, 116, 235, 10.1016/S0092-8674(03)01075-4 Zhang, 2000, Wild-type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression, Cancer Res, 60, 3655 Zhang, 2005, Oncogenes as novel targets for cancer therapy (part I): growth factors and protein tyrosine kinases, Am J Pharmacogenomics, 5, 173, 10.2165/00129785-200505030-00004 Rak, 1995, Oncogenes as inducers of tumor angiogenesis, Cancer Metastasis Rev, 14, 263, 10.1007/BF00690598 Qi, 2005, MAP kinase pathways, J Cell Sci, 118, 3569, 10.1242/jcs.02470 Thompson, 1989, Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ, Cell, 56, 917, 10.1016/0092-8674(89)90625-9 Grugel, 1995, Both v-Ha-Ras and v-Raf stimulate expression of the vascular endothelial growth factor in NIH 3T3 cells, J Biol Chem, 270, 25915, 10.1074/jbc.270.43.25915 Sassone-Corsi, 1988, Direct interaction between fos and jun nuclear oncoproteins: role of the ‘leucine zipper’ domain, Nature, 336, 692, 10.1038/336692a0 Whitmarsh, 1996, Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways, J Mol Med, 74, 589, 10.1007/s001090050063 Xie, 2004, Constitutive and inducible expression and regulation of vascular endothelial growth factor, Cytokine Growth Factor Rev, 15, 297, 10.1016/j.cytogfr.2004.04.003 Rak, 1995, Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis, Cancer Res, 55, 4575 Arbiser, 1997, Oncogenic H-ras stimulates tumor angiogenesis by two distinct pathways, Proc Natl Acad Sci USA, 94, 861, 10.1073/pnas.94.3.861 Kranenburg, 2004, Stimulation of angiogenesis by Ras proteins, Biochim Biophys Acta, 1654, 23 Konishi, 2000, The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers, Int J Oncol, 16, 501 Ikeda, 2001, The association of K-ras gene mutation and vascular endothelial growth factor gene expression in pancreatic carcinoma, Cancer, 92, 488, 10.1002/1097-0142(20010801)92:3<488::AID-CNCR1347>3.0.CO;2-F Folkman, 2003, Fundamental concepts of the angiogenic process, Curr Mol Med, 3, 643, 10.2174/1566524033479465 Folkman, 1971, Tumor angiogenesis: therapeutic implications, N Engl J Med, 285, 1182, 10.1056/NEJM197111182852108 Dailey, 2005, Mechanisms underlying differential responses to FGF signaling, Cytokine Growth Factor Rev, 16, 233, 10.1016/j.cytogfr.2005.01.007 Ferrara, 1997, The biology of vascular endothelial growth factor, Endocr Rev, 18, 4, 10.1210/er.18.1.4 Dvorak, 1991, Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels, J Exp Med, 174, 1275, 10.1084/jem.174.5.1275 Jubb, 2006, Predicting benefit from anti-angiogenic agents in malignancy, Nat Rev Cancer, 6, 626, 10.1038/nrc1946 Kim, 1993, Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo, Nature, 362, 841, 10.1038/362841a0 Muller, 1998, VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4Å resolution and mutational analysis of the interface, Structure, 6, 1153, 10.1016/S0969-2126(98)00116-6 Liang, 2006, Cross-species vascular endothelial growth factor (VEGF)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal VEGF, J Biol Chem, 281, 951, 10.1074/jbc.M508199200 Jubb, 2006, Impact of vascular endothelial growth factor-A expression, thrombospondin-2 expression, and microvessel density on the treatment effect of bevacizumab in metastatic colorectal cancer, J Clin Oncol, 24, 217, 10.1200/JCO.2005.01.5388 Ferrara, 2005, Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy, Biochem Biophys Res Commun, 333, 328, 10.1016/j.bbrc.2005.05.132 Amato, 2005, Renal cell carcinoma: review of novel single-agent therapeutics and combination regimens, Ann Oncol, 16, 7, 10.1093/annonc/mdi002 Ranieri, 2006, Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic, Curr Med Chem, 13, 1845, 10.2174/092986706777585059 Ruegg, 2006, Antiangiogenic peptides and proteins: From experimental tools to clinical drugs, Biochim Biophys Acta, 1765, 155 de Castro Junior, 2006, Angiogenesis and cancer: a cross-talk between basic science and clinical trials (the “do ut des” paradigm), Crit Rev Oncol Hematol, 59, 40, 10.1016/j.critrevonc.2006.02.007 Gridelli, 2006, New antiangiogenetic agents and non-small cell lung cancer, Crit Rev Oncol Hematol, 60, 76, 10.1016/j.critrevonc.2006.01.008 Wilhelm, 2006, Discovery and development of sorafenib: a multikinase inhibitor for treating cancer, Nat Rev Drug Discov, 5, 835, 10.1038/nrd2130 Wilhelm, 2004, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis, Cancer Res, 64, 7099, 10.1158/0008-5472.CAN-04-1443 Cabebe, 2006, Sunitinib: a newly approved small-molecule inhibitor of angiogenesis, Drugs Today (Barc), 42, 387, 10.1358/dot.2006.42.6.985633 Manley, 2004, Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis, Biochim Biophys Acta, 1697, 17, 10.1016/j.bbapap.2003.11.010 Roskoski, 2005, Structure and regulation of Kit protein-tyrosine kinase—the stem cell factor receptor, Biochem Biophys Res Commun, 338, 1307, 10.1016/j.bbrc.2005.09.150 Hiratsuka, 2002, MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis, Cancer Cell, 2, 289, 10.1016/S1535-6108(02)00153-8 Kaplan, 2005, VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche, Nature, 438, 820, 10.1038/nature04186 Kamba, 2006, VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature, Am J Physiol Heart Circ Physiol, 290, H560, 10.1152/ajpheart.00133.2005 von Tell, 2006, Pericytes and vascular stability, Exp Cell Res, 312, 623, 10.1016/j.yexcr.2005.10.019 Sanborn, 2006, The safety of bevacizumab, Expert Opin Drug Saf, 5, 289, 10.1517/14740338.5.2.289 Faivre, 2006, Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer, J Clin Oncol, 24, 25, 10.1200/JCO.2005.02.2194 Veronese, 2006, Mechanisms of hypertension associated with BAY 43-9006, J Clin Oncol, 24, 1363, 10.1200/JCO.2005.02.0503 Ferrara, 2007, Targeting VEGF-A to treat cancer and age-related macular degeneration, Annu Rev Med, 58, 491, 10.1146/annurev.med.58.061705.145635 Jain, 2006, Lessons from phase III clinical trials on anti-VEGF therapy for cancer, Nat Clin Pract Oncol, 3, 24, 10.1038/ncponc0403