Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma
The high mortality rate of melanoma is broadly associated with its metastatic potential. 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 vascul...
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doaj-59bfc539d44a4f09aa3897f829666aba2020-11-25T03:22:10ZengWileyMolecular Oncology1574-78911878-02612019-06-011361433144910.1002/1878-0261.12501Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanomaAna Carolina Monteiro0Julienne K. Muenzner1Fernando Andrade2Flávia Eichemberger Rius3Christian Ostalecki4Carol I. Geppert5Abbas Agaimy6Arndt Hartmann7André Fujita8Regine Schneider‐Stock9Miriam Galvonas Jasiulionis10Department of Pharmacology Escola Paulista de Medicina Universidade Federal de São Paulo BrazilDepartment of Experimental Tumor Pathology Institute of Pathology Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU) GermanyDepartment of Computer Science Institute of Mathematics and Statistics Universidade de São Paulo BrazilDepartment of Pharmacology Escola Paulista de Medicina Universidade Federal de São Paulo BrazilDepartment of Dermatology Friedrich‐Alexander Universität Erlangen‐Nürnberg (FAU) Universitätsklinikum Erlangen GermanyInstitute of Pathology Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU) GermanyInstitute of Pathology Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU) GermanyInstitute of Pathology Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU) GermanyDepartment of Computer Science Institute of Mathematics and Statistics Universidade de São Paulo BrazilDepartment of Experimental Tumor Pathology Institute of Pathology Friedrich‐Alexander‐Universität Erlangen‐Nürnberg (FAU) GermanyDepartment of Pharmacology Escola Paulista de Medicina Universidade Federal de São Paulo BrazilThe high mortality rate of melanoma is broadly associated with its metastatic potential. 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 Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P‐value = 0.044) and the lymphangiogenic receptor VEGFR‐3 (P‐value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing‐based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P‐value = 0.031), ANGPT2 (P‐value < 0.001), and SIX1 (P‐value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio‐ 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.https://doi.org/10.1002/1878-0261.12501angiogenesisbiomarkersDNA methylationmelanomaprognosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ana Carolina Monteiro Julienne K. Muenzner Fernando Andrade Flávia Eichemberger Rius Christian Ostalecki Carol I. Geppert Abbas Agaimy Arndt Hartmann André Fujita Regine Schneider‐Stock Miriam Galvonas Jasiulionis |
spellingShingle |
Ana Carolina Monteiro Julienne K. Muenzner Fernando Andrade Flávia Eichemberger Rius Christian Ostalecki Carol I. Geppert Abbas Agaimy Arndt Hartmann André Fujita Regine Schneider‐Stock Miriam Galvonas Jasiulionis Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma Molecular Oncology angiogenesis biomarkers DNA methylation melanoma prognosis |
author_facet |
Ana Carolina Monteiro Julienne K. Muenzner Fernando Andrade Flávia Eichemberger Rius Christian Ostalecki Carol I. Geppert Abbas Agaimy Arndt Hartmann André Fujita Regine Schneider‐Stock Miriam Galvonas Jasiulionis |
author_sort |
Ana Carolina Monteiro |
title |
Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
title_short |
Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
title_full |
Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
title_fullStr |
Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
title_full_unstemmed |
Gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
title_sort |
gene expression and promoter methylation of angiogenic and lymphangiogenic factors as prognostic markers in melanoma |
publisher |
Wiley |
series |
Molecular Oncology |
issn |
1574-7891 1878-0261 |
publishDate |
2019-06-01 |
description |
The high mortality rate of melanoma is broadly associated with its metastatic potential. 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 Vegfc, Angpt2, and Six1, and that blockade of the vascular endothelial growth factor pathway by the inhibitor axitinib abrogates their tumorigenic potential in vitro and in the in vivo chicken chorioallantoic membrane assay. Furthermore, analysis of The Cancer Genome Atlas data revealed that the expression of the angiogenic factor ANGPT2 (P‐value = 0.044) and the lymphangiogenic receptor VEGFR‐3 (P‐value = 0.002) were independent prognostic factors of overall survival in melanoma patients. Enhanced reduced representation bisulfite sequencing‐based methylome profiling revealed for the first time a link between abnormal VEGFC, ANGPT2, and SIX1 gene expression and promoter hypomethylation in melanoma cells. In patients, VEGFC (P‐value = 0.031), ANGPT2 (P‐value < 0.001), and SIX1 (P‐value = 0.009) promoter hypomethylation were independent prognostic factors of shorter overall survival. Hence, our data suggest that these angio‐ 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. |
topic |
angiogenesis biomarkers DNA methylation melanoma prognosis |
url |
https://doi.org/10.1002/1878-0261.12501 |
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