Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer.

Vascular endothelial growth factors (VEGFs) are critical regulators of vascular and lymphatic function during development, in health and in disease. There are five mammalian VEGF ligands and three VEGF receptor tyrosine kinases. In addition, several VEGF co-receptors that lack intrinsic catalytic activity, but that indirectly modulate the responsiveness to VEGF contribute to the final biological effect. This review describes the molecular features of VEGFs, VEGFRs and co-receptors with focus on their role in the treatment of cancer.

[1]  Steven J. Harper,et al.  VEGF-A splicing: the key to anti-angiogenic therapeutics? , 2008, Nature Reviews Cancer.

[2]  I. Kasman,et al.  Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy , 2010, Clinical Cancer Research.

[3]  J. Floege,et al.  Renal side effects of anti-VEGF therapy in man: a new test system. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[4]  D. Hicklin,et al.  Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. , 1999, Cancer research.

[5]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[6]  J. Boivin,et al.  Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling. , 2011, Journal of hepatology.

[7]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[8]  J. Ambati,et al.  Neuroblastoma Progression Correlates with Downregulation of the Lymphangiogenesis Inhibitor sVEGFR-2 , 2010, Clinical Cancer Research.

[9]  Ingeborg Stalmans,et al.  Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. , 2002, The Journal of clinical investigation.

[10]  H. Granger,et al.  Placenta growth factor-1 is chemotactic, mitogenic, and angiogenic. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[11]  E. Perez,et al.  Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. , 2007, The New England journal of medicine.

[12]  G. Tortora,et al.  Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Human Cancer Cells with Acquired Resistance to Antiepidermal Growth Factor Receptor Therapy , 2004, Clinical Cancer Research.

[13]  Lena Claesson-Welsh,et al.  Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. , 2006, Experimental cell research.

[14]  Rakesh K. Jain,et al.  Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy , 2001, Nature Medicine.

[15]  J. Martin Collinson,et al.  Corneal avascularity is due to soluble VEGF receptor-1 , 2006, Nature.

[16]  Frederik De Smet,et al.  Branching morphogenesis and antiangiogenesis candidates: tip cells lead the way , 2009, Nature Reviews Clinical Oncology.

[17]  D. Goldenberg,et al.  Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement , 2010, British Journal of Cancer.

[18]  S. Rafii,et al.  Contribution of marrow-derived progenitors to vascular and cardiac regeneration. , 2002, Seminars in cell & developmental biology.

[19]  D. Ribatti,et al.  Expression and Functions of the Vascular Endothelial Growth Factors and Their Receptors in Human Basophils1 , 2006, The Journal of Immunology.

[20]  A. Ullrich,et al.  High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis , 1993, Cell.

[21]  Alex L Kolodkin,et al.  Neuropilin Is a Semaphorin III Receptor , 1997, Cell.

[22]  M. Shibuya,et al.  Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. , 1990, Oncogene.

[23]  Holger Gerhardt,et al.  How do endothelial cells orientate? , 2005, EXS.

[24]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[25]  George Coukos,et al.  Tumor vascular proteins as biomarkers in ovarian cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  H. Verheul,et al.  Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? , 2009, Angiogenesis.

[27]  Y. Bang,et al.  Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. , 2011, The New England journal of medicine.

[28]  A. Wilks,et al.  NYK/FLK-1: a putative receptor protein tyrosine kinase isolated from E10 embryonic neuroepithelium is expressed in endothelial cells of the developing embryo. , 1993, Oncogene.

[29]  Franklin Peale,et al.  Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. , 2007, Cancer cell.

[30]  W. Arap,et al.  Targeting neuropilin-1 in human leukemia and lymphoma. , 2011, Blood.

[31]  P. Frankel,et al.  Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas , 2011, The Biochemical journal.

[32]  Bo Hu,et al.  Identification of two novel alternatively spliced Neuropilin-1 isoforms. , 2004, Genomics.

[33]  M. Neurath,et al.  VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer , 2010, The Journal of experimental medicine.

[34]  Chiun Hsu,et al.  Serum Vascular Endothelial Growth Factor/Soluble Vascular Endothelial Growth Factor Receptor 1 Ratio Is an Independent Prognostic Marker in Pancreatic Cancer , 2008, Pancreas.

[35]  Ruslan Hlushchuk,et al.  Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance , 2004, Developmental dynamics : an official publication of the American Association of Anatomists.

[36]  Zhao-You Tang,et al.  Expression and prognostic significance of placental growth factor in hepatocellular carcinoma and peritumoral liver tissue , 2011, International journal of cancer.

[37]  M. Crépin,et al.  Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. , 2006, Life sciences.

[38]  J. Foidart,et al.  Soluble forms of VEGF receptor‐1 and ‐2 promote vascular maturation via mural cell recruitment , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  M. Kasper,et al.  Apoptosis of human macrophages by Flt-4 signaling: implications for atherosclerotic plaque pathology. , 2006, Cardiovascular research.

[40]  R. Tibshirani,et al.  Lymphoma cell VEGFR2 expression detected by immunohistochemistry predicts poor overall survival in diffuse large B cell lymphoma treated with immunochemotherapy (R‐CHOP) , 2010, British journal of haematology.

[41]  L. Ellis,et al.  Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases , 2000, Cancer.

[42]  M. Ratner.  Fearful of Avastin's fate, Genentech asks for unusual hearing , 2011, Nature Medicine.

[43]  M. Fernö,et al.  Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up , 2010, Breast Cancer Research and Treatment.

[44]  C. Sternberg,et al.  Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  J. Folkman,et al.  Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice. , 2001, Journal of the National Cancer Institute.

[46]  Betty Y. Y. Tam,et al.  VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. , 2006, American journal of physiology. Heart and circulatory physiology.

[47]  K. Podar,et al.  The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. , 2005, Blood.

[48]  N. Normanno,et al.  Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors. , 2010, IDrugs : the investigational drugs journal.

[49]  J. Adams,et al.  A strategy for the design of multiplex inhibitors for kinase-mediated signalling in angiogenesis. , 2002, Current opinion in chemical biology.

[50]  G. Yancopoulos,et al.  New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF , 1999, Oncogene.

[51]  T. Morita,et al.  C-Terminal Heparin-Binding Peptide of Snake Venom VEGF Specifically Blocks VEGF-Stimulated Endothelial Cell Proliferation , 2006, Pathophysiology of Haemostasis and Thrombosis.

[52]  W. Yung,et al.  Bevacizumab and Irinotecan in the Treatment of Recurrent Malignant Gliomas , 2008, Cancer journal.

[53]  R. Moritz,et al.  Biosynthesis of Vascular Endothelial Growth Factor-D Involves Proteolytic Processing Which Generates Non-covalent Homodimers* , 1999, The Journal of Biological Chemistry.

[54]  Sushanta K Banerjee,et al.  Neuropilin‐1 is differentially expressed in myoepithelial cells and vascular smooth muscle cells in preneoplastic and neoplastic human breast: A possible marker for the progression of breast cancer , 2002, International journal of cancer.

[55]  Masakazu,et al.  Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor‐1 relationship in breast cancer , 2002, International journal of cancer.

[56]  D. Mukhopadhyay,et al.  Neuropilin-1-mediated Vascular Permeability Factor/Vascular Endothelial Growth Factor-dependent Endothelial Cell Migration* , 2003, Journal of Biological Chemistry.

[57]  Kenneth J. Hillan,et al.  Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene , 1996, Nature.

[58]  K. Alitalo,et al.  Vascular Endothelial Growth Factor-B–Deficient Mice Display an Atrial Conduction Defect , 2001, Circulation.

[59]  A. Sulkes.  Novel multitargeted anticancer oral therapies: sunitinib and sorafenib as a paradigm. , 2010, The Israel Medical Association journal : IMAJ.

[60]  J. Ambati,et al.  Alternatively spliced VEGF receptor-2 is an essential endogenous inhibitor of lymphatic vessels , 2009, Nature Medicine.

[61]  J. Mestan,et al.  PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. , 2000, Cancer research.

[62]  D. Carbone,et al.  VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. , 2003, Blood.

[63]  K. Devriendt,et al.  Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. , 2000, American journal of human genetics.

[64]  N. Petrelli,et al.  Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  C. Allerston,et al.  Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction† , 2010, Journal of medicinal chemistry.

[66]  B. Curry,et al.  ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. , 2002, Cancer research.

[67]  M. Shibuya,et al.  A Novel Type of Vascular Endothelial Growth Factor, VEGF-E (NZ-7 VEGF), Preferentially Utilizes KDR/Flk-1 Receptor and Carries a Potent Mitotic Activity without Heparin-binding Domain* , 1998, The Journal of Biological Chemistry.

[68]  B. Skov,et al.  Biomarkers in tissue from patients with upper gastrointestinal cancers treated with erlotinib and bevacizumab , 2011, Cancer biology & therapy.

[69]  W. Zhan,et al.  The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma. , 2010, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[70]  A. N. Corps,et al.  A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. , 1998, Biology of reproduction.

[71]  Kristian Pietras,et al.  A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Lars Jakobsson,et al.  Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization. , 2008, Blood.

[73]  H Ueno,et al.  The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. , 1992, Science.

[74]  M. Tessier-Lavigne,et al.  Neuropilin Is a Receptor for the Axonal Chemorepellent Semaphorin III , 1997, Cell.

[75]  Masato Nakamura,et al.  Neuropilin 1 and neuropilin 2 co‐expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma , 2002, Cancer.

[76]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[77]  M. Thomas.  Toward improved outcomes in hepatocellular carcinoma: overcoming the challenges of an "orphan" tumor. , 2009, Gastrointestinal cancer research : GCR.

[78]  M. Giacca,et al.  Anti-PlGF Inhibits Growth of VEGF(R)-Inhibitor-Resistant Tumors without Affecting Healthy Vessels , 2007, Cell.

[79]  B. Frediani,et al.  Vascular Endothelial Growth Factor-D Activates VEGFR-3 Expressed in Osteoblasts Inducing Their Differentiation* , 2006, Journal of Biological Chemistry.

[80]  R. Mansel,et al.  Expression of Placenta growth factor (PlGF) in non-Small cell Lung cancer (NSCLC) and the clinical and prognostic significance , 2005, World journal of surgical oncology.

[81]  R. Jain,et al.  VEGFR1 Activity Modulates Myeloid Cell Infiltration in Growing Lung Metastases but Is Not Required for Spontaneous Metastasis Formation , 2009, PloS one.

[82]  J. Breed,et al.  Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[84]  N. Normanno,et al.  Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. , 2009, The oncologist.

[85]  G. Neufeld,et al.  Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. , 2006, Blood.

[86]  M. Shibuya,et al.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. , 2002, Cancer cell.

[87]  Shenhong Wu,et al.  Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. , 2010, American journal of hypertension.

[88]  Masato Nakamura,et al.  The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer. , 2006, Oncology reports.

[89]  L. Ellis,et al.  Neuropilin-2–Mediated Tumor Growth and Angiogenesis in Pancreatic Adenocarcinoma , 2008, Clinical Cancer Research.

[90]  Franklin Peale,et al.  Neuropilin-1 Binds to VEGF121 and Regulates Endothelial Cell Migration and Sprouting* , 2007, Journal of Biological Chemistry.

[91]  Lena Claesson-Welsh,et al.  Claesson-Welsh L: Vascular endothelial growth factor (VEGF)-A165b is a weak in vitro agonist for VEGF receptor-2 due to lack of coreceptor binding and deficient regulation of kinase activity , 2022 .

[92]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[93]  L. Teng,et al.  Clinical Applications of VEGF‐Trap (Aflibercept) in Cancer Treatment , 2010, Journal of the Chinese Medical Association : JCMA.

[94]  H. Bellamy,et al.  Structural basis for ligand and heparin binding to neuropilin B domains , 2007, Proceedings of the National Academy of Sciences.

[95]  S. Rafii,et al.  Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue , 2006, Current opinion in hematology.

[96]  K. Alitalo,et al.  Neural guidance molecules regulate vascular remodeling and vessel navigation. , 2005, Genes & development.

[97]  S. Ryu,et al.  Anti-neuropilin-1 peptide inhibition of synoviocyte survival, angiogenesis, and experimental arthritis. , 2010, Arthritis and rheumatism.

[98]  A. Bleyer,et al.  Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial. , 2010, Journal of the National Cancer Institute.

[99]  Olivier Hermine,et al.  A neuronal receptor, neuropilin-1, is essential for the initiation of the primary immune response , 2002, Nature Immunology.

[100]  T. Libermann,et al.  Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia , 2003 .

[101]  T. Chikama,et al.  Expression of semaphorin 3A and its receptors during mouse corneal development. , 2010, Biochemical and biophysical research communications.

[102]  J. Folkman.  Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[103]  Wadih Arap,et al.  From combinatorial peptide selection to drug prototype (I): Targeting the vascular endothelial growth factor receptor pathway , 2010, Proceedings of the National Academy of Sciences.

[104]  Efstathios Karathanasis,et al.  Tumor Vascular Permeability to a Nanoprobe Correlates to Tumor-Specific Expression Levels of Angiogenic Markers , 2009, PloS one.

[105]  Takafumi Yoshida,et al.  The ratio of serum placenta growth factor to soluble vascular endothelial growth factor receptor-1 predicts the prognosis of hepatocellular carcinoma. , 2010, Oncology reports.

[106]  B. Skov,et al.  Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: relation to prognosis. , 2009 .

[107]  T. Choueiri,et al.  Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. , 2009, The Lancet. Oncology.

[108]  J. Spratlin.  Ramucirumab (IMC-1121B): Monoclonal Antibody Inhibition of Vascular Endothelial Growth Factor Receptor-2 , 2011, Current oncology reports.

[109]  N. Ferrara,et al.  Differential Transcriptional Regulation of the Two Vascular Endothelial Growth Factor Receptor Genes , 1997, The Journal of Biological Chemistry.

[110]  T. Kitsukawa,et al.  Receptors for collapsin/semaphorins , 1998, Current Opinion in Neurobiology.

[111]  Seppo Ylä-Herttuala,et al.  Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3 , 2001, Nature Medicine.

[112]  R. Swann,et al.  Vascular Endothelial Growth Factor Receptors VEGFR-2 and VEGFR-3 Are Localized Primarily to the Vasculature in Human Primary Solid Cancers , 2010, Clinical Cancer Research.

[113]  Ge Li,et al.  Anti-Flt1 Peptide, a Vascular Endothelial Growth Factor Receptor 1–Specific Hexapeptide, Inhibits Tumor Growth and Metastasis , 2005, Clinical Cancer Research.

[114]  Ming-Chih Crouthamel,et al.  Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors , 2009, British Journal of Cancer.

[115]  K. Alitalo,et al.  Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. , 2007, Cancer research.

[116]  Richard D Schulick,et al.  Expression of Neuropilin-1 in High-grade Dysplasia, Invasive Cancer, and Metastases of the Human Gastrointestinal Tract , 2004, The American journal of surgical pathology.

[117]  H. Kikutani,et al.  Neuropilin-1: the glue between regulatory T cells and dendritic cells? , 2008, Immunity.

[118]  B. Keyt,et al.  Solution structure of the heparin-binding domain of vascular endothelial growth factor. , 1998, Structure.

[119]  H. Dvorak,et al.  Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. , 1983, Science.

[120]  S. Mousa,et al.  Antiangiogenic and antimetastatic properties of Neovastat (Æ-941), an orally active extract derived from cartilage tissue , 2004, Clinical & Experimental Metastasis.

[121]  M. Ladomery,et al.  Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors , 2008, Journal of Cell Science.

[122]  G. Neufeld,et al.  The semaphorins: versatile regulators of tumour progression and tumour angiogenesis , 2008, Nature Reviews Cancer.

[123]  Georg Bartsch,et al.  Combined antiangiogenic therapy is superior to single inhibitors in a model of renal cell carcinoma. , 2008, The Journal of urology.

[124]  K. Alitalo,et al.  Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. , 1998, Science.

[125]  D. Rimm,et al.  High levels of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome in breast cancer. , 2008, Human Pathology.

[126]  M. Shibuya,et al.  VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis , 2010, Cell Research.

[127]  F. Peale,et al.  Cross-species Vascular Endothelial Growth Factor (VEGF)-blocking Antibodies Completely Inhibit the Growth of Human Tumor Xenografts and Measure the Contribution of Stromal VEGF* , 2006, Journal of Biological Chemistry.

[128]  T. Taxt,et al.  Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma , 2011, Proceedings of the National Academy of Sciences.

[129]  K. Alitalo,et al.  VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. , 1996, Development.

[130]  Till Acker,et al.  Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions , 2001, Nature Medicine.

[131]  Thijs J. Hagenbeek,et al.  PlGF Blockade Does Not Inhibit Angiogenesis during Primary Tumor Growth , 2010, Cell.

[132]  Laura A. Sullivan,et al.  r84, a Novel Therapeutic Antibody against Mouse and Human VEGF with Potent Anti-Tumor Activity and Limited Toxicity Induction , 2010, PloS one.

[133]  A. Luttun,et al.  Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1 , 2002, Nature Medicine.

[134]  H. Augustin,et al.  Neuropilin‐1 and neuropilin‐2 enhance VEGF121 stimulated signal transduction by the VEGFR‐2 receptor , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[135]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[136]  H. Dvorak.  Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[137]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[138]  M. Hori,et al.  Glycosaminoglycan modification of neuropilin‐1 modulates VEGFR2 signaling , 2006, The EMBO journal.

[139]  I. Vlodavsky,et al.  Tumorigenic and adhesive properties of heparanase. , 2010, Seminars in cancer biology.

[140]  Curzio Ruegg,et al.  Anti-angiogenic therapies in cancer: achievements and open questions. , 2007, Bulletin du cancer.

[141]  G. Kay,et al.  Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. , 2000, Circulation research.

[142]  L. Claesson‐Welsh,et al.  Signal transduction by vascular endothelial growth factor receptors. , 2011, The Biochemical journal.

[143]  F. Kabbinavar,et al.  Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[144]  H. Wakelee,et al.  Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer. , 2009, Current opinion in investigational drugs.

[145]  Kenneth P. Roos,et al.  Autocrine VEGF Signaling Is Required for Vascular Homeostasis , 2007, Cell.

[146]  K. Alitalo,et al.  Lymphangiogenesis: Molecular Mechanisms and Future Promise , 2010, Cell.

[147]  R. Kelly,et al.  Target Inhibition in Antiangiogenic Therapy A Wide Spectrum of Selectivity and Specificity , 2010, Cancer journal.

[148]  L. Siu,et al.  Brivanib alaninate for cancer , 2011, Expert opinion on investigational drugs.

[149]  R. Kauppinen,et al.  A model for gene therapy of human hereditary lymphedema , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[150]  Napoleone Ferrara,et al.  VEGF as a Therapeutic Target in Cancer , 2005, Oncology.

[151]  A. Bikfalvi,et al.  Molecular mechanisms of tumor vascularization. , 2005, Critical reviews in oncology/hematology.

[152]  T. Noda,et al.  Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[153]  K. Alitalo,et al.  Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. , 2000, The American journal of pathology.

[154]  J. Chesnes,et al.  VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. , 2008, Cancer cell.

[155]  M. Karkkainen,et al.  Preexisting Lymphatic Endothelium but not Endothelial Progenitor Cells Are Essential for Tumor Lymphangiogenesis and Lymphatic Metastasis , 2004, Cancer Research.

[156]  T. Eisen,et al.  Impact of anti-angiogenic treatments on metastatic renal cell carcinoma , 2009, Expert review of anticancer therapy.

[157]  S. Stacker,et al.  Molecular Control of Lymphatic Metastasis , 2008, Annals of the New York Academy of Sciences.

[158]  R. Dana,et al.  Growth Factors , Cytokines , Cell Cycle Molecules Contribution of Macrophages to Angiogenesis Induced by Vascular Endothelial Growth Factor Receptor-3-Specific Ligands , 2010 .

[159]  K. Alitalo,et al.  Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. , 2010, Cancer cell.

[160]  Elisabeth Brambilla,et al.  Expression of VEGF, semaphorin SEMA3F, and their common receptors neuropilins NP1 and NP2 in preinvasive bronchial lesions, lung tumours, and cell lines , 2003, The Journal of pathology.

[161]  T. Roskams,et al.  High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile , 2007, British Journal of Cancer.

[162]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[163]  I. Giannopoulou,et al.  The prognostic value of vascular endothelial growth factors (VEGFs)-A and -B and their receptor, VEGFR-1, in invasive breast carcinoma. , 2007, Gynecologic oncology.

[164]  Shenhong Wu,et al.  Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. , 2011, JAMA.

[165]  D. Hicklin,et al.  Simultaneous blockade of VEGFR‐1 and VEGFR‐2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation , 2007, International journal of cancer.

[166]  I. Zachary.  Signaling mechanisms mediating vascular protective actions of vascular endothelial growth factor. , 2001, American journal of physiology. Cell physiology.

[167]  S. Groshen,et al.  Phase I study of antisense oligonucleotide against vascular endothelial growth factor: decrease in plasma vascular endothelial growth factor with potential clinical efficacy. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[168]  R. Kendall,et al.  Specificity of vascular endothelial cell growth factor receptor ligand binding domains. , 1994, Biochemical and biophysical research communications.

[169]  K. Alitalo,et al.  The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. , 2008, Cancer research.

[170]  Victoria L. Bautch,et al.  The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching , 2008, The Journal of cell biology.

[171]  E. D. de Vries,et al.  Prognostic versus predictive value of biomarkers in oncology. , 2008, European journal of cancer.

[172]  A. Ullrich,et al.  Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. , 1993, Cancer research.

[173]  Xin Huang,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[174]  G. Conn,et al.  Purification and Characterization of a Naturally Occurring Vascular Endothelial Growth Factor · Placenta Growth Factor Heterodimer (*) , 1995, The Journal of Biological Chemistry.

[175]  R. Herbst,et al.  Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. , 2011, The Journal of clinical investigation.

[176]  O. Stoeltzing,et al.  Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells , 2005, British Journal of Cancer.

[177]  J. Rossant,et al.  Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium , 1995, Nature.

[178]  M. Karkkainen,et al.  Abnormal lymphatic vessel development in neuropilin 2 mutant mice. , 2002, Development.

[179]  F. Larcher,et al.  Modulation of the angiogenesis response through Ha‐ras control, placenta growth factor, and angiopoietin expression in mouse skin carcinogenesis , 2003, Molecular carcinogenesis.

[180]  F. Hsieh,et al.  Placenta growth factor expression is correlated with survival of patients with colorectal cancer , 2005, Gut.

[181]  K. Alitalo,et al.  VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts , 2010, The EMBO journal.

[182]  J. Esko,et al.  Heparan Sulfate Regulates VEGF165- and VEGF121-mediated Vascular Hyperpermeability* , 2010, The Journal of Biological Chemistry.

[183]  D. Aunis,et al.  Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo , 2010, Oncogene.

[184]  Alice P. Taylor,et al.  Role of placenta growth factor in malignancy and evidence that an antagonistic PlGF/Flt-1 peptide inhibits the growth and metastasis of human breast cancer xenografts , 2007, Molecular Cancer Therapeutics.

[185]  S. Rafii,et al.  Inhibition of human leukemia in an animal model with human antibodies directed against vascular endothelial growth factor receptor 2. Correlation between antibody affinity and biological activity , 2003, Leukemia.

[186]  F. Peale,et al.  Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies , 2007, Proceedings of the National Academy of Sciences.

[187]  G. Neufeld,et al.  Gene expression pattern Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins , 2001 .

[188]  R. Jain,et al.  VEGFR1-activity-independent metastasis formation , 2009, Nature.

[189]  R. Porcher,et al.  Quantification of VEGF isoforms and VEGFR transcripts by qRT-PCR and their significance in acute myeloid leukemia. , 2009, The International journal of biological markers.

[190]  L. Williams,et al.  Vascular endothelial growth factor receptor expression during embryogenesis and tissue repair suggests a role in endothelial differentiation and blood vessel growth. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[191]  S. Grimm,et al.  Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[192]  Fabian Kiessling,et al.  Flt-1 signaling in macrophages promotes glioma growth in vivo. , 2008, Cancer research.

[193]  Janet Rossant,et al.  Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice , 1995, Nature.

[194]  R. Moritz,et al.  Plasmin Activates the Lymphangiogenic Growth Factors VEGF-C and VEGF-D , 2003, The Journal of experimental medicine.

[195]  S. Soker,et al.  Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[196]  J. Cassidy,et al.  Current status of cediranib: the rapid development of a novel anti-angiogenic therapy. , 2009, Future oncology.

[197]  K. Chayama,et al.  Neuropilin-1 is involved in regulation of apoptosis and migration of human colon cancer. , 2006, International journal of oncology.

[198]  G. Zambruno,et al.  Placenta growth factor is induced in human keratinocytes during wound healing. , 2000, The Journal of investigative dermatology.

[199]  J. Zentner,et al.  Implications of Vascular Endothelial Growth Factor, sFlt-1, and sTie-2 in Plasma, Serum and Cerebrospinal Fluid during Cerebral Ischemia in Man , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[200]  P. Carmeliet,et al.  Lessons from the adjuvant bevacizumab trial on colon cancer: what next? , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[201]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[202]  N. Yamamoto,et al.  A molecular mechanism that regulates medially oriented axonal growth of upper layer neurons in the developing neocortex , 2011, The Journal of comparative neurology.

[203]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[204]  E. Small,et al.  Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[205]  T. Quinn,et al.  Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[206]  K. Alitalo,et al.  Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. , 2005, Cancer research.

[207]  P. Carmeliet,et al.  VEGF-C is a trophic factor for neural progenitors in the vertebrate embryonic brain , 2006, Nature Neuroscience.

[208]  M. Kanda,et al.  Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico‐pathological parameters , 2008, Journal of surgical oncology.

[209]  H. Cai,et al.  Cloning and Characterization of Neuropilin-1-Interacting Protein: A PSD-95/Dlg/ZO-1 Domain-Containing Protein That Interacts with the Cytoplasmic Domain of Neuropilin-1 , 1999, The Journal of Neuroscience.

[210]  Masahiro Inoue,et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. , 2009, Cancer cell.

[211]  T. Noda,et al.  Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis. , 2001, Cancer research.

[212]  Amir Abdollahi,et al.  Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. , 2010, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[213]  D. McDonald,et al.  Cellular abnormalities of blood vessels as targets in cancer. , 2005, Current opinion in genetics & development.

[214]  D. Hanahan,et al.  Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. , 2003, The Journal of clinical investigation.

[215]  K. Garcia,et al.  The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. , 2000, The Journal of biological chemistry.

[216]  Robert E. Ferrell,et al.  Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema , 2000, Nature Genetics.

[217]  T. Mok,et al.  Randomized, open-label phase II study of motesanib or bevacizumab in combination with paclitaxel and carboplatin (P/C) for advanced nonsquamous non-small cell lung cancer (NSCLC). , 2010 .

[218]  A. Ullrich,et al.  Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant , 1994, Nature.

[219]  B. Keyt,et al.  Identification of Vascular Endothelial Growth Factor Determinants for Binding KDR and FLT-1 Receptors , 1996, The Journal of Biological Chemistry.

[220]  I. Kasman,et al.  PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. , 2009, Cancer cell.

[221]  D. McDonald,et al.  Rapid vascular regrowth in tumors after reversal of VEGF inhibition. , 2006, The Journal of clinical investigation.

[222]  R. Motzer,et al.  Sunitinib efficacy against advanced renal cell carcinoma. , 2007, The Journal of urology.

[223]  D. Carbone,et al.  Differential Roles of Vascular Endothelial Growth Factor Receptors 1 and 2 in Dendritic Cell Differentiation1 , 2005, The Journal of Immunology.

[224]  R. Wang,et al.  Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model , 2008, BMC Cancer.

[225]  M. Shibuya,et al.  Inhibition of choroidal neovascularization by blocking vascular endothelial growth factor receptor tyrosine kinase , 2008, Japanese Journal of Ophthalmology.

[226]  K. Uematsu,et al.  Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer. , 2006, Lung cancer.

[227]  A. Eggert,et al.  High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[228]  E. Hildt,et al.  New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication , 2009, Gut.

[229]  J. Mulliken,et al.  Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations , 2006, Clinical genetics.

[230]  R. Porcher,et al.  Soluble Isoforms of Vascular Endothelial Growth Factor Are Predictors of Response to Sunitinib in Metastatic Renal Cell Carcinomas , 2010, PloS one.

[231]  K. Alitalo,et al.  Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[232]  B. Li,et al.  Requirements for Binding and Signaling of the Kinase Domain Receptor for Vascular Endothelial Growth Factor* , 1998, The Journal of Biological Chemistry.

[233]  Wing-Kai Chan,et al.  Targeting Neuropilin 1 as an Antitumor Strategy in Lung Cancer , 2007, Clinical Cancer Research.

[234]  A. Verin,et al.  Neuropilin-1 Regulates Vascular Endothelial Growth Factor–Mediated Endothelial Permeability , 2005, Circulation research.

[235]  L. Ellis,et al.  Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[236]  B. Seliger,et al.  Antitumour and immune-adjuvant activities of protein-tyrosine kinase inhibitors. , 2010, Trends in molecular medicine.

[237]  Yihai Cao,et al.  Proteolytic processing regulates receptor specificity and activity of VEGF‐C , 1997, The EMBO journal.

[238]  F. Peale,et al.  Blocking neuropilin-2 function inhibits tumor cell metastasis. , 2008, Cancer cell.

[239]  H. Dvorak,et al.  Vascular permeability, vascular hyperpermeability and angiogenesis , 2008, Angiogenesis.

[240]  M. Shibuya,et al.  Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. , 2006, Blood.

[241]  P. Kelly,et al.  High-grade glioma before and after treatment with radiation and Avastin: initial observations. , 2008, Neuro-oncology.

[242]  M. Klagsbrun,et al.  The role of neuropilin in vascular and tumor biology. , 2002, Advances in experimental medicine and biology.

[243]  M. Shibuya,et al.  Vascular Endothelial Growth Factor Receptor-1 and Neuropilin-2 Form Complexes* , 2001, The Journal of Biological Chemistry.

[244]  John M L Ebos,et al.  Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. , 2009, Cancer cell.

[245]  K. Kinzler,et al.  Genes expressed in human tumor endothelium. , 2000, Science.

[246]  Konstantin V Balakin,et al.  VEGF/VEGFR signalling as a target for inhibiting angiogenesis , 2007, Expert opinion on investigational drugs.

[247]  G. Neufeld,et al.  Neuropilin‐2 is a novel marker expressed in pancreatic islet cells and endocrine pancreatic tumours , 2002, The Journal of pathology.

[248]  J. Folkman,et al.  Clinical translation of angiogenesis inhibitors , 2002, Nature Reviews Cancer.

[249]  J. Wood,et al.  A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2 , 2006, Cellular and Molecular Life Sciences CMLS.

[250]  J. Verweij,et al.  Multitarget tyrosine kinase inhibition: [and the winner is...]. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[251]  I. Zachary,et al.  Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivity , 2010, British Journal of Cancer.

[252]  Holger Gerhardt,et al.  Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. , 2002, Genes & development.

[253]  M. Giacca,et al.  Further Pharmacological and Genetic Evidence for the Efficacy of PlGF Inhibition in Cancer and Eye Disease , 2010, Cell.

[254]  G. Yancopoulos,et al.  VEGF-Trap: A VEGF blocker with potent antitumor effects , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[255]  Jeffrey W. Clark,et al.  Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. , 2009, Cancer research.

[256]  T. Kitsukawa,et al.  Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[257]  K. Alitalo,et al.  VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. , 2000, Blood.

[258]  Napoleone Ferrara,et al.  Angiogenesis as a therapeutic target , 2005, Nature.

[259]  Gabriele Bergers,et al.  Modes of resistance to anti-angiogenic therapy , 2008, Nature Reviews Cancer.

[260]  J. Denekamp.  Vascular attack as a therapeutic strategy for cancer , 1990, Cancer and Metastasis Reviews.

[261]  M. Nomura,et al.  Placenta Growth Factor and Vascular Endothelial Growth Factor B and C Expression in Microvascular Endothelial Cells and Pericytes , 1999, The Journal of Biological Chemistry.

[262]  Feng Zhang,et al.  Prognostic significance and potential therapeutic target of VEGFR2 in hepatocellular carcinoma , 2011, Journal of Clinical Pathology.

[263]  H. Izzedine,et al.  Macrocytosis due to treatment with sunitinib. , 2007, The New England journal of medicine.

[264]  J. Thrasher,et al.  Differential expression of neuropilin-1 in malignant and benign prostatic stromal tissue. , 2003, Oncology reports.

[265]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[266]  B. Teicher,et al.  sFLT01: A Novel Fusion Protein with Antiangiogenic Activity , 2011, Molecular Cancer Therapeutics.

[267]  H. Matsumoto,et al.  Overexpression of soluble vascular endothelial growth factor receptor 1 in colorectal cancer: Association with progression and prognosis , 2007, Cancer science.

[268]  J. Soria,et al.  VEGF signalling inhibition-induced proteinuria: Mechanisms, significance and management. , 2010, European journal of cancer.

[269]  S. Sleijfer,et al.  (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. , 2010, The oncologist.

[270]  S. Stone-Elander,et al.  Vascular endothelial growth factor B controls endothelial fatty acid uptake , 2010, Nature.

[271]  G. Meinhardt,et al.  Vatalanib: the clinical development of a tyrosine kinase inhibitor of angiogenesis in solid tumours , 2007, Expert opinion on investigational drugs.

[272]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[273]  J. Winer,et al.  Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. , 1992, The Journal of clinical investigation.

[274]  Bohuslav Melichar,et al.  Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial , 2007, The Lancet.

[275]  M. Karkkainen,et al.  The Specificity of Receptor Binding by Vascular Endothelial Growth Factor-D Is Different in Mouse and Man* , 2001, The Journal of Biological Chemistry.

[276]  O. Cussenot,et al.  VEGF overexpression in clinically localized prostate tumors and neuropilin‐1 overexpression in metastatic forms , 2000, International journal of cancer.

[277]  Antonio Duarte,et al.  Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation , 2008, Nature.

[278]  K. Sunagawa,et al.  Essential Role of Vascular Endothelial Growth Factor and Flt-1 Signals in Neointimal Formation After Periadventitial Injury , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[279]  Y. Kimura,et al.  Epiadryamicin concentration in experimental hepatic metastases after bolus or continous infusion through systemic or locoregional routes. , 2003 .

[280]  Jun Cai,et al.  Placenta growth factor is over-expressed and has prognostic value in human breast cancer. , 2005, European journal of cancer.

[281]  Peter Carmeliet,et al.  VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[282]  A Shinkai,et al.  Mapping of the Sites Involved in Ligand Association and Dissociation at the Extracellular Domain of the Kinase Insert Domain-containing Receptor for Vascular Endothelial Growth Factor* , 1998, The Journal of Biological Chemistry.

[283]  W. Falk,et al.  Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. , 2009, Arthritis and rheumatism.

[284]  M. Shibuya,et al.  Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. , 2010, Cancer research.

[285]  D. Hicklin,et al.  Review: Monoclonal Antibodies to the Vascular Endothelial Growth Factor Receptor-2 in Cancer Therapy , 2007, Clinical Cancer Research.

[286]  D. Hicklin,et al.  Anti-Vascular Endothelial Growth Factor Receptor-1 Antagonist Antibody as a Therapeutic Agent for Cancer , 2006, Clinical Cancer Research.

[287]  Baoshan Xu,et al.  The fungicide ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway , 2010, Oncogene.

[288]  J. White.  The challenge of rational development of complex natural products as cancer therapeutics. , 2010, Journal of the National Cancer Institute.

[289]  B. Monk,et al.  Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[290]  D. Carbone,et al.  Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells , 1996, Nature Medicine.

[291]  T. Yagi,et al.  A requirement for neuropilin-1 in embryonic vessel formation. , 1999, Development.

[292]  Dirk Strumberg,et al.  Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment. , 2005, Drugs of today.

[293]  Ricky T. Tong,et al.  Placenta growth factor overexpression inhibits tumor growth, angiogenesis, and metastasis by depleting vascular endothelial growth factor homodimers in orthotopic mouse models. , 2006, Cancer research.

[294]  E. Keshet,et al.  Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis , 1992, Nature.

[295]  K. Okuda,et al.  Expression of VEGF and its receptors in the bovine endometrium throughout the estrous cycle: effects of VEGF on prostaglandin production in endometrial cells. , 2010, The Journal of reproduction and development.

[296]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[297]  H. Baelde,et al.  Role of the VEGF-A Signaling Pathway in the Glomerulus: Evidence for Crosstalk between Components of the Glomerular Filtration Barrier , 2007, Nephron Physiology.

[298]  D. Schadendorf,et al.  Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma , 2010, The Journal of Experimental Medicine.

[299]  M. Shibuya,et al.  VEGFR-1 Signaling Regulates the Homing of Bone Marrow-Derived Cells in a Mouse Stroke Model , 2010, Journal of neuropathology and experimental neurology.

[300]  Robert S. Kerbel,et al.  The anti-angiogenic basis of metronomic chemotherapy , 2004, Nature Reviews Cancer.

[301]  S. Wilhelm,et al.  Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. , 2006, Methods in enzymology.

[302]  Edward S. Kim,et al.  Bevacizumab: current updates in treatment , 2010, Current opinion in oncology.

[303]  S. Soker,et al.  In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. , 2002, Blood.

[304]  Masakazu Toi,et al.  Angiogenic inhibitors: a new therapeutic strategy in oncology , 2005, Nature Clinical Practice Oncology.

[305]  D. Nettelbeck,et al.  Adenovirus-mediated soluble FLT-1 gene therapy for ovarian carcinoma. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[306]  S. Rafii,et al.  Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow microenvironment , 2002, Nature Medicine.

[307]  S. Fox,et al.  VEGF‐B expression in human primary breast cancers is associated with lymph node metastasis but not angiogenesis , 2001, The Journal of pathology.

[308]  Shay Soker,et al.  Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor , 1998, Cell.

[309]  John A Butman,et al.  Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[310]  Jaume Bosch,et al.  Angiogenesis in liver disease. , 2009, Journal of hepatology.

[311]  Dai Fukumura,et al.  Tumor microenvironment abnormalities: Causes, consequences, and strategies to normalize , 2007, Journal of cellular biochemistry.

[312]  C. Goodman,et al.  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 , 1997, Neuron.

[313]  L. Ellis,et al.  Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. , 2008, Journal of the National Cancer Institute.

[314]  R. Kerbel,et al.  'Accidental' anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. , 2000, European journal of cancer.

[315]  H. Dvorak.  Discovery of vascular permeability factor (VPF). , 2006, Experimental cell research.

[316]  R. Kendall,et al.  Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[317]  Manal M. Hassan,et al.  Vascular endothelial growth factor in the management of hepatocellular carcinoma , 2009, Cancer.

[318]  M. Sekine,et al.  Vascular Endothelial Growth Factor Mediates Intracrine Survival in Human Breast Carcinoma Cells through Internally Expressed VEGFR1/FLT1 , 2007, PLoS medicine.

[319]  Jianhua Huang,et al.  A Role for VEGF as a Negative Regulator of Pericyte Function and Vessel Maturation , 2008, Nature.