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Tumor cell dissemination is strictly dependent on vascularization; therefore, angiogenesis and lymphangiogenesis play an essential role in metastasis. Hence, a better understanding of the players of tumor vascularization and establishing them as new molecular biomarkers might help to overcome the poor prognosis of melanoma patients. Here, we further characterized a linear murine model of melanoma progression and showed that the aggressiveness of melanoma cells is closely associated with high expression of angiogenic factors, such as <jats:italic>Vegfc<\/jats:italic>,<jats:italic> Angpt2, and Six1,<\/jats:italic> and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential <jats:italic>in\u00a0vitro<\/jats:italic> and in the <jats:italic>in\u00a0vivo<\/jats:italic> chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor <jats:italic>ANGPT2<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.044) and the lymphangiogenic receptor <jats:italic>VEGFR\u20103<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing\u2010based methylome profiling revealed for the first time a link between abnormal <jats:italic>VEGFC<\/jats:italic>,<jats:italic> ANGPT2,<\/jats:italic> and <jats:italic>SIX1<\/jats:italic> gene expression and promoter hypomethylation in melanoma cells. In patients, <jats:italic>VEGFC<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.031), <jats:italic>ANGPT2<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2010value &lt;\u00a00.001), and <jats:italic>SIX1<\/jats:italic> (<jats:italic>P<\/jats:italic>\u2010value\u00a0=\u00a00.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio\u2010 and lymphangiogenesis factors are potential biomarkers of melanoma prognosis. Moreover, these findings strongly support the applicability of our melanoma progression model to unravel new biomarkers for this aggressive human disease.<\/jats:p>","DOI":"10.1002\/1878-0261.12501","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T06:44:39Z","timestamp":1557384279000},"page":"1433-1449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Ana Carolina","family":"Monteiro","sequence":"first","affiliation":[{"name":"Department of Pharmacology Escola Paulista de Medicina Universidade Federal de S\u00e3o Paulo Brazil"},{"name":"Department of Experimental Tumor Pathology Institute of Pathology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) 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Friedrich\u2010Alexander Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) Universit\u00e4tsklinikum Erlangen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol I.","family":"Geppert","sequence":"additional","affiliation":[{"name":"Institute of Pathology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abbas","family":"Agaimy","sequence":"additional","affiliation":[{"name":"Institute of Pathology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arndt","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg (FAU) 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