{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:29:21Z","timestamp":1788388161151,"version":"build-2803163510"},"reference-count":96,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,2,17]],"date-time":"2018-02-17T00:00:00Z","timestamp":1518825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Experimental evidence has associated receptor tyrosine kinase EphB4 with tumor angiogenesis also in malignant melanoma. Considering the limited in vivo data available, we have conducted a systematic multitracer and multimodal imaging investigation in EphB4-overexpressing and mock-transfected A375 melanoma xenografts. Tumor growth, perfusion, and hypoxia were investigated by positron emission tomography. Vascularization was investigated by fluorescence imaging in vivo and ex vivo. The approach was completed by magnetic resonance imaging, radioluminography ex vivo, and immunohistochemical staining for blood and lymph vessel markers. Results revealed EphB4 to be a positive regulator of A375 melanoma growth, but a negative regulator of tumor vascularization. Resulting in increased hypoxia, this physiological characteristic is considered as highly unfavorable for melanoma prognosis and therapy outcome. Lymphangiogenesis, by contrast, was not influenced by EphB4 overexpression. In order to distinguish between EphB4 forward and EphrinB2, the natural EphB4 ligand, reverse signaling a specific EphB4 kinase inhibitor was applied. Blocking experiments show EphrinB2 reverse signaling rather than EphB4 forward signaling to be responsible for the observed effects. In conclusion, functional expression of EphB4 is considered a promising differentiating characteristic, preferentially determined by non-invasive in vivo imaging, which may improve personalized theranostics of malignant melanoma.<\/jats:p>","DOI":"10.3390\/molecules23020444","type":"journal-article","created":{"date-parts":[[2018,2,20]],"date-time":"2018-02-20T03:54:22Z","timestamp":1519098862000},"page":"444","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Overexpression of Receptor Tyrosine Kinase EphB4 Triggers Tumor Growth and Hypoxia in A375 Melanoma Xenografts: Insights from Multitracer Small Animal Imaging Experiments"],"prefix":"10.3390","volume":"23","author":[{"given":"Christin","family":"Neuber","sequence":"first","affiliation":[{"name":"Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Belter","sequence":"additional","affiliation":[{"name":"Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Meister","sequence":"additional","affiliation":[{"name":"Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8733-4286","authenticated-orcid":false,"given":"Frank","family":"Hofheinz","sequence":"additional","affiliation":[{"name":"Department Positron Emission Tomography, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-J\u00fcrgen","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Department Radionuclide Theragnostics, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1610-1493","authenticated-orcid":false,"given":"Jens","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Department Radiopharmaceutical and Chemical Biology, Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01314 Dresden, Germany"},{"name":"Faculty of Chemistry and Food Chemistry, School of Science, Technische Universit\u00e4t Dresden, 01062 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1586\/era.11.25","article-title":"Therapy for metastatic melanoma: an overview and update","volume":"11","author":"Boyle","year":"2011","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1007\/s00726-012-1409-5","article-title":"Protein and non-protein biomarkers in melanoma: a critical update","volume":"43","author":"Tandler","year":"2012","journal-title":"Amino Acids"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3172","DOI":"10.1038\/sj.onc.1206457","article-title":"Angiogenesis, lymphangiogenesis, and melanoma metastasis","volume":"22","author":"Streit","year":"2003","journal-title":"Oncogene"},{"key":"ref_4","first-page":"5962","article-title":"Vascular endothelial growth factor C mRNA expression correlates with stage of progression in patients with melanoma","volume":"9","author":"Goydos","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1056\/NEJM197111182852108","article-title":"Tumor angiogenesis: therapeutic implications","volume":"285","author":"Folkman","year":"1971","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/S0002-9440(10)64328-3","article-title":"Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival","volume":"162","author":"Dadras","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1038\/modpathol.3800410","article-title":"Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes","volume":"18","author":"Dadras","year":"2005","journal-title":"Mod. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/jcp.21494","article-title":"Tumor lymphangiogenesis and melanoma metastasis","volume":"216","author":"Rinderknecht","year":"2008","journal-title":"J. Cell. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1111\/j.1582-4934.2009.00834.x","article-title":"Lymphangiogenesis and cancer metastasis","volume":"13","author":"Mumprecht","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1200\/JCO.2001.19.2.577","article-title":"Increased serum concentration of angiogenic factors in malignant melanoma patients correlates with tumor progression and survival","volume":"19","author":"Ugurel","year":"2001","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1097\/00008390-200208000-00004","article-title":"VEGF-165 serum levels and tyrosinase expression in melanoma patients: correlation with the clinical course","volume":"12","author":"Quaglino","year":"2002","journal-title":"Melanoma Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.ejca.2008.12.015","article-title":"Tumoural expression and circulating level of VEGFR-3 (Flt-4) in metastatic melanoma patients: correlation with clinical parameters and outcome","volume":"45","author":"Mouawad","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.humpath.2009.08.016","article-title":"Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays","volume":"41","author":"Mehnert","year":"2010","journal-title":"Hum. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/156802612798919240","article-title":"The role of angiogenesis inhibitors in the management of melanoma","volume":"12","author":"Zaki","year":"2012","journal-title":"Curr. Top Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/PPO.0b013e318178d9de","article-title":"Targeting angiogenesis driven by vascular endothelial growth factors using antibody-based therapies","volume":"14","author":"Grothey","year":"2008","journal-title":"Cancer J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrd1381","article-title":"Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer","volume":"3","author":"Ferrara","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1358\/dot.2005.41.12.937959","article-title":"Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment","volume":"41","author":"Strumberg","year":"2005","journal-title":"Drugs Today"},{"key":"ref_18","first-page":"327","article-title":"In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic\/pharmacodynamic relationship","volume":"9","author":"Mendel","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4632","DOI":"10.1021\/jm800566m","article-title":"Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor","volume":"51","author":"Harris","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/sj.bjc.6604929","article-title":"Why are tumour blood vessels abnormal and why is it important to know?","volume":"100","author":"Nagy","year":"2009","journal-title":"Brit. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1055\/s-0030-1253454","article-title":"Heterogeneity of the tumor vasculature","volume":"36","author":"Nagy","year":"2010","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_22","first-page":"4324","article-title":"Absence of functional lymphatics within a murine sarcoma: A molecular and functional evaluation","volume":"60","author":"Leu","year":"2000","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1126\/science.1071420","article-title":"Lymphatic metastasis in the absence of functional intratumor lymphatics","volume":"296","author":"Padera","year":"2002","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrc1893","article-title":"Drug penetration in solid tumours","volume":"6","author":"Minchinton","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/nm0901-987","article-title":"Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy","volume":"7","author":"Jain","year":"2001","journal-title":"Nat. Med."},{"key":"ref_26","first-page":"4185","article-title":"Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: Effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts","volume":"58","author":"Oku","year":"1998","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1084\/jem.20020072","article-title":"Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis","volume":"195","author":"Li","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1016\/S0140-6736(11)60545-X","article-title":"Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): A double-blind, placebo-controlled, phase 3 trial","volume":"377","author":"Herbst","year":"2011","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1056\/NEJMoa1103799","article-title":"A Phase 3 Trial of Bevacizumab in Ovarian Cancer","volume":"365","author":"Perren","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/S1470-2045(15)00086-8","article-title":"Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial","volume":"16","author":"Oza","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"135285","DOI":"10.1155\/2010\/135285","article-title":"Eph receptors and ephrin ligands: important players in angiogenesis and tumor angiogenesis","volume":"2010","author":"Mosch","year":"2010","journal-title":"J. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S0092-8674(00)81436-1","article-title":"Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4","volume":"93","author":"Wang","year":"1998","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1101\/gad.13.3.295","article-title":"Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial\/venous domains, vascular morphogenesis, and sprouting angiogenesis","volume":"13","author":"Adams","year":"1999","journal-title":"Gene Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S1097-2765(00)80342-1","article-title":"Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development","volume":"4","author":"Gerety","year":"1999","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1242\/dev.129.6.1397","article-title":"Cardiovascular ephrinB2 function is essential for embryonic angiogenesis","volume":"129","author":"Gerety","year":"2002","journal-title":"Development"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1101\/gad.330105","article-title":"PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature","volume":"19","author":"Makinen","year":"2005","journal-title":"Gene Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.cell.2005.10.034","article-title":"Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly","volume":"124","author":"Foo","year":"2006","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0092-8674(01)00191-X","article-title":"The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration","volume":"104","author":"Adams","year":"2001","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1089\/lrb.2008.1005","article-title":"Lymphatic endothelial cells, lymphedematous lymphangiogenesis, and molecular control of edema formation","volume":"6","author":"Ji","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature09002","article-title":"Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis","volume":"465","author":"Wang","year":"2010","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nature08995","article-title":"Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis","volume":"465","author":"Sawamiphak","year":"2010","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1073\/pnas.0401381101","article-title":"Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth","volume":"101","author":"Noren","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.yexmp.2016.03.011","article-title":"EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer","volume":"100","author":"Lv","year":"2016","journal-title":"Exp. Mol. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1007\/s12032-013-0572-1","article-title":"Gene expression profiling identifies EPHB4 as a potential predictive biomarker in colorectal cancer patients treated with bevacizumab","volume":"30","author":"Sanchez","year":"2013","journal-title":"Med. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2353\/ajpath.2006.050889","article-title":"Receptor tyrosine kinase EphB4 is a survival factor in breast cancer","volume":"169","author":"Kumar","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Stephenson, S.A., Slomka, S., Douglas, E.L., Hewett, P.J., and Hardingham, J.E. (2001). Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol. Biol., 2.","DOI":"10.1186\/1471-2199-2-15"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/cncr.10122","article-title":"Coexpression of ephrin-Bs and their receptors in colon carcinoma","volume":"94","author":"Liu","year":"2002","journal-title":"Cancer."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1093\/annonc\/mdg072","article-title":"Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma","volume":"14","author":"Berclaz","year":"2003","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lee, Y.C., Perren, J.R., Douglas, E.L., Raynor, M.P., Bartley, M.A., Bardy, P.G., and Stephenson, S.A. (2005). Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma. BMC Cancer, 5.","DOI":"10.1186\/1471-2407-5-119"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10709","DOI":"10.1158\/0008-5472.CAN-06-1327","article-title":"New potential ligand-receptor signaling loops in ovarian cancer identified in multiple gene expression studies","volume":"66","author":"Castellano","year":"2006","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jphs.2015.08.009","article-title":"EphB4 inhibitor overcome the acquired resistance to cisplatin in melanomas xenograft model","volume":"129","author":"Yang","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2147\/HP.S93413","article-title":"The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy","volume":"3","author":"Muz","year":"2015","journal-title":"Hypoxia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1097\/CMR.0b013e32835e58f3","article-title":"Experimental hypoxia does not influence gene expression and protein synthesis of Eph receptors and ephrin ligands in human melanoma cells in vitro","volume":"23","author":"Reissenweber","year":"2013","journal-title":"Melanoma Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"517","DOI":"10.2967\/jnumed.107.048504","article-title":"Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: A comparison with 15O-labeled water measured blood flow","volume":"49","author":"Mullani","year":"2008","journal-title":"J. Nucl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2967\/jnumed.114.148106","article-title":"Whole-body PET\/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): Validation by direct comparison to 15O-water in metastatic renal cell carcinoma","volume":"56","author":"Fletcher","year":"2015","journal-title":"J. Nucl. Med."},{"key":"ref_56","first-page":"379","article-title":"Copper-64 radiopharmaceuticals for PET imaging of cancer: Advances in preclinical and clinical research","volume":"24","author":"Anderson","year":"2009","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s10456-010-9183-z","article-title":"The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis","volume":"13","author":"Holzer","year":"2010","journal-title":"Angiogenesis"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1002\/cmdc.201200264","article-title":"Fluorine-18 radiolabeling and radiopharmacological characterization of a benzodioxolylpyrimidine-based radiotracer targeting the receptor tyrosine kinase EphB4","volume":"7","author":"Mamat","year":"2012","journal-title":"ChemMedChem"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"32574","DOI":"10.1074\/jbc.M604338200","article-title":"The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization","volume":"281","author":"Yang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1111\/j.1755-148X.2010.00745.x","article-title":"The EphB4 receptor promotes the growth of melanoma cells expressing the ephrin-B2 ligand","volume":"23","author":"Yang","year":"2010","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9800","DOI":"10.1158\/0008-5472.CAN-07-0531","article-title":"EphB4 overexpression in B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis","volume":"67","author":"Huang","year":"2007","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.1158\/0008-5472.CAN-07-0525","article-title":"Paradoxes of the EphB4 receptor in cancer","volume":"67","author":"Pasquale","year":"2007","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"E614","DOI":"10.1002\/ijc.27392","article-title":"Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand","volume":"131","author":"Rutkowski","year":"2012","journal-title":"Int. J. Cancer."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1593\/neo.03457","article-title":"Inhibition of tumor growth and angiogenesis by soluble EphB4","volume":"6","author":"Korff","year":"2004","journal-title":"Neoplasia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1158\/1541-7786.MCR-09-0453","article-title":"EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell-expressed ephrinB2","volume":"8","author":"Heroult","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_66","first-page":"791","article-title":"Overexpression of Lerk-5\/Eplg5 messenger RNA: A novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas","volume":"4","author":"Vogt","year":"1998","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1038\/sj.bjc.6601723","article-title":"Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer","volume":"90","author":"Liu","year":"2004","journal-title":"Brit. J. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.nucmedbio.2007.01.002","article-title":"Assessment of Cu-ETS as a PET radiopharmaceutical for evaluation of regional renal perfusion","volume":"34","author":"Green","year":"2007","journal-title":"Nucl. Med. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.nucmedbio.2007.11.009","article-title":"Species dependence of [64Cu]Cu-Bis(thiosemicarbazone) radiopharmaceutical binding to serum albumins","volume":"35","author":"Basken","year":"2008","journal-title":"Nucl. Med. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1148\/radiol.2423052065","article-title":"Tomographic fluorescence imaging of tumor vascular volume in mice","volume":"242","author":"Montet","year":"2007","journal-title":"Radiology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1158\/1535-7163.MCT-11-0008","article-title":"Time-course imaging of therapeutic functional tumor vascular normalization by antiangiogenic agents","volume":"10","author":"Zhang","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/bjc.1988.54","article-title":"Validation of the fluorescent dye Hoechst 33342 as a vascular space marker in tumors","volume":"57","author":"Smith","year":"1988","journal-title":"Brit. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1242\/dev.022475","article-title":"Artery and vein size is balanced by Notch and ephrin B2\/EphB4 during angiogenesis","volume":"135","author":"Kim","year":"2008","journal-title":"Development"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0360-3016(92)91001-4","article-title":"Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole","volume":"22","author":"Koh","year":"1992","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20150014","DOI":"10.1259\/bjr.20150014","article-title":"Validation of functional imaging as a biomarker for radiation treatment response","volume":"88","author":"Jentsch","year":"2015","journal-title":"Brit. J. Radiol."},{"key":"ref_76","first-page":"1010","article-title":"Nitric oxide-releasing selective cyclooxygenase-2 inhibitors as promising radiosensitizers in melanoma cells in vitro","volume":"1","author":"Bechmann","year":"2017","journal-title":"Ann. Radiat. Ther. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"442","DOI":"10.2174\/156652409788167087","article-title":"Hypoxia and radiation therapy: Past history, ongoing research, and future promise","volume":"9","author":"Rockwell","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3389\/fonc.2017.00010","article-title":"Assessing tumor oxygenation for predicting outcome in radiation oncology: A review of studies correlating tumor hypoxic status and outcome in the preclinical and clinical settings","volume":"7","author":"Colliez","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1083\/jcb.144.4.789","article-title":"LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan","volume":"144","author":"Banerji","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1471-4906(01)01936-6","article-title":"LYVE-1, the lymphatic system and tumor lymphangiogenesis","volume":"22","author":"Jackson","year":"2001","journal-title":"Trends Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/nm0710-752","article-title":"VEGF and ephrin-B2: a bloody duo","volume":"16","author":"Germain","year":"2010","journal-title":"Nat. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.2353\/ajpath.2010.090755","article-title":"Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth","volume":"176","author":"Krasnoperov","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1182\/blood-2011-09-380006","article-title":"Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth","volume":"119","author":"Abengozar","year":"2012","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4161\/cam.20655","article-title":"Irradiation affects cellular properties and Eph receptor expression in human melanoma cells","volume":"6","author":"Mosch","year":"2012","journal-title":"Cell Adhes. Migr."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.7150\/thno.16614","article-title":"Gelatin-based Hydrogel Degradation and Tissue Interaction in vivo: Insights from Multimodal Preclinical Imaging in Immunocompetent Nude Mice","volume":"6","author":"Tondera","year":"2016","journal-title":"Theranostics"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1605189","DOI":"10.1002\/adfm.201605189","article-title":"In vivo examination of an injectable hydrogel system crosslinked by peptide-oligosaccharide interaction in immunocompetent nude mice","volume":"27","author":"Tondera","year":"2017","journal-title":"Adv. Funct. Mater."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1016\/j.bmc.2012.04.022","article-title":"Radiosynthesis of a \u00b9\u2078F-labeled 2,3-diarylsubstituted indole via McMurry coupling for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo","volume":"20","author":"Kniess","year":"2012","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S1095-0397(00)00065-0","article-title":"First pass FDG measured blood flow in tumors: A comparison with O-15 labeled water measured blood flow","volume":"3","author":"Mullani","year":"2000","journal-title":"Clin. Positron. Imaging."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/jcbfm.1985.87","article-title":"Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data","volume":"5","author":"Patlak","year":"1985","journal-title":"Gen. J. Cereb. Blood Flow Metab."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1118\/1.597506","article-title":"A modeling approach for quantifying tumor hypoxia with [F-18]fluoromisonidazole PET time-activity data","volume":"22","author":"Casciari","year":"1995","journal-title":"Med. Phys."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s11307-017-1083-9","article-title":"Quantification of tumor hypoxic fractions using positron emission tomography with [18F]fluoromisonidazole ([18F]FMISO) kinetic analysis and invasive oxygen measurements","volume":"19","author":"Kelada","year":"2017","journal-title":"Mol. Imaging Biol."},{"key":"ref_92","unstructured":"RCoreTeam (2014). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1016\/j.bmc.2015.06.040","article-title":"Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers","volume":"23","author":"Ebert","year":"2015","journal-title":"Biorg. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/jlcr.3526","article-title":"Preparation of a novel radiotracer targeting the EphB4 receptor via radiofluorination using spiro azetidinium salts as precursor","volume":"60","author":"Wiemer","year":"2017","journal-title":"J. Label. Compd. Radiopharm."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Ward, W.H., and Farma, J.M. (2017). Biomarkers in malignant melanoma: recent trends and critical perspective. Cutaneous Melanoma: Etiology and Therapy, Codon Publications.","DOI":"10.15586\/codon.cutaneousmelanoma.2017"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/2\/444\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:55:28Z","timestamp":1760194528000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/2\/444"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,17]]},"references-count":96,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,2]]}},"alternative-id":["molecules23020444"],"URL":"https:\/\/doi.org\/10.3390\/molecules23020444","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,17]]}}}