{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:45:45Z","timestamp":1783647945112,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,4,9]],"date-time":"2015-04-09T00:00:00Z","timestamp":1428537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant melanoma (MM) urgently needs identification of new markers with better predictive value than currently-used clinical and histological parameters. Cancer cells stimulate the formation of a specialized tumor microenvironment, which reciprocally affects uncontrolled proliferation and migration. However, this microenvironment is heterogeneous with different sub-compartments defined by their access to oxygen and nutrients. This study evaluated microvascular density (MVD), CD3+ lymphocytes (TILs) and FOXP3+ T-regulatory lymphocytes (Tregs) on formalin-fixed paraffin-embedded tissue sections using light microscopy. We analyzed 82 malignant melanomas, divided according to the AJCC TNM classification into four groups\u2014pT1 (35), pT2 (17), pT3 (18) and pT4 (12)\u2014and 25 benign pigmented nevi. All parameters were measured in both the central areas of tumors (C) and at their periphery (P). A marked increase in all parameters was found in melanomas compared to nevi (p = 0.0001). There was a positive correlation between MVD, TILs, FOXP3+ Tregs and the vertical growth phase. The results show that MVD, TILs and FOXP3+ Tregs substantially influence cutaneous melanoma microenvironment. We found significant topographic differences of the parameters between central areas of tumors and their boundaries.<\/jats:p>","DOI":"10.3390\/ijms16047876","type":"journal-article","created":{"date-parts":[[2015,4,9]],"date-time":"2015-04-09T10:44:31Z","timestamp":1428576271000},"page":"7876-7889","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Changes of Angiogenesis and Immune Cell Infiltration in the Intra- and Peri-Tumoral Melanoma Microenvironment"],"prefix":"10.3390","volume":"16","author":[{"given":"Vladimir","family":"Zidlik","sequence":"first","affiliation":[{"name":"CGB Laboratory, a.s., Laboratory of Molecular Genetics and Pathology, AGEL Research and Training Institute\u2014Ostrava-Vitkovice Branch, Korenskeho 10, Ostrava 71000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Brychtova","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry,  Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Uvirova","sequence":"additional","affiliation":[{"name":"CGB Laboratory, a.s., Laboratory of Molecular Genetics and Pathology, AGEL Research and Training Institute\u2014Ostrava-Vitkovice Branch, Korenskeho 10, Ostrava 71000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dusan","family":"Ziak","sequence":"additional","affiliation":[{"name":"CGB Laboratory, a.s., Laboratory of Molecular Genetics and Pathology, AGEL Research and Training Institute\u2014Ostrava-Vitkovice Branch, Korenskeho 10, Ostrava 71000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Dvorackova","sequence":"additional","affiliation":[{"name":"CGB Laboratory, a.s., Laboratory of Molecular Genetics and Pathology, AGEL Research and Training Institute\u2014Ostrava-Vitkovice Branch, Korenskeho 10, Ostrava 71000, Czech Republic"},{"name":"Department of Pathology, Faculty of Medicine, University of Ostrava, Syllabova 19,  Ostrava 70300, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/bjd.13171","article-title":"Prognostic factors in localized invasive primary cutaneous malignant melanoma: Results of a large population-based study","volume":"172","author":"Eriksson","year":"2015","journal-title":"Br. J. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1097\/PAT.0b013e328363b3bd","article-title":"Melanoma\u2019s connections to the tumour microenvironment","volume":"45","author":"Brandner","year":"2013","journal-title":"Pathology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1158\/0008-5472.CAN-12-4115","article-title":"Melanoma-educated CD14+ cells acquire a myeloid-derive suppressor cell phenotype through COX-2-dependent mechanisms","volume":"73","author":"Mao","year":"2013","journal-title":"Cancer Res."},{"key":"ref_4","first-page":"601","article-title":"Evaluation of microvascular density in tumors, pro and contra","volume":"23","author":"Nico","year":"2008","journal-title":"Histol. Histopathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3748\/wjg.v19.i1.42","article-title":"Nestin: A novel angiogenesis marker and possible target for tumor angiogenesis","volume":"19","author":"Matsuda","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ria, R., Reale, A., Castrovilli, A., Mangialardi, G., Dammacco, F., Ribatti, D., and Vacca, A. (2010). Angiogenesis and prognosis in human melanoma. Dermatol. Res. Pract., 2010, Article ID 185687.","DOI":"10.1155\/2010\/185687"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1136\/jcp.2004.021238","article-title":"Nestin as a diagnostic and prognostic marker: Immunohistochemical analysis of its expression in different tumours","volume":"58","author":"Ehrmann","year":"2005","journal-title":"J. Clin. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/j.1600-0560.2006.00627.x","article-title":"Nestin expression in cutaneous melanomas and melanocytic nevi","volume":"34","author":"Brychtova","year":"2007","journal-title":"J. Cutan. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.5507\/bp.2010.048","article-title":"Identification of CD133+\/nestin+ putative cancer stem cells in non-small cell lung cancer","volume":"154","author":"Janikova","year":"2010","journal-title":"Biomed. Pap. Med. Fac. Univ. Palacky Olomouc. Czech Repub."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kretschmer, S., Dethlefsen, I., Hagner-Benes, S., Marsch, L.M., Garn, H., and K\u00f6nig, P. (2013). Visualization of intrapulmonary lymph vessels in healthy and inflamed murine lung using CD90\/Thy-1 as a marker. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055201"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1016\/j.yexcr.2010.06.013","article-title":"Thymus cell antigen 1 (Thy1, CD90) is expressed by lymphatic vessels and mediates cell adhesion to lymphatic endothelium","volume":"316","author":"Jurisic","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.ajpath.2012.10.003","article-title":"Melanoma cells use Thy-1 (CD90) on endothelial cells for metastasis formation","volume":"182","author":"Schubert","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4710","DOI":"10.1038\/sj.onc.1208559","article-title":"Interaction of human Thy-1 (CD90) with the integrin \u03b1v\u03b23 (CD51\/CD61): An important mechanism mediating melanoma cell adhesion to activated endothelium","volume":"24","author":"Saalbach","year":"2005","journal-title":"Oncogene"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/bjd.12641","article-title":"High expression of FOXP3 in primary melanoma is associated with tumour progression","volume":"170","author":"Gerber","year":"2014","journal-title":"Br. J. Dermathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.canlet.2006.12.036","article-title":"Vasculogenic mimicry: Current status and future prospects","volume":"254","author":"Zhang","year":"2007","journal-title":"Cancer Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1002\/ijc.25464","article-title":"Prognostic significance of regulatory T cells in tumor","volume":"127","author":"Wilke","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1007\/s00262-011-1025-3","article-title":"Foxp3 expression in melanoma cells as a possible mechanism of resistance to immune destruction","volume":"60","author":"Niu","year":"2011","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jss.2007.03.053","article-title":"Melanoma induces immunosuppression by upregulating FOXP3+ regulatory T cells","volume":"141","author":"Baumgartner","year":"2007","journal-title":"J. Surg. Res."},{"key":"ref_19","first-page":"11","article-title":"Tumor infiltrating lymphocytes: An intriguing player in the survival of colorectal cancer patients","volume":"12","author":"Deschoolmeester","year":"2010","journal-title":"BMC Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00262-002-0276-4","article-title":"The role of CD8+ T cells in immune responses to colorectal cancer","volume":"51","author":"Titu","year":"2002","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_21","first-page":"369","article-title":"The immune system and cancer","volume":"24","author":"Loose","year":"2009","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/labinvest.3700389","article-title":"Tumor-infiltrating T lymphocytes: Friends or foes?","volume":"86","author":"Yu","year":"2006","journal-title":"Lab. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1146\/annurev-med-112311-083918","article-title":"Harnessing the power of the immune system to target cancer","volume":"64","author":"Lizee","year":"2013","journal-title":"Annu. Rev. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/modpathol.2012.43","article-title":"Immune response in melanoma: An in-depth analysis of the primary tumor and corresponding sentinel lymph node","volume":"25","author":"Ma","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1097\/01.sla.0000247058.43243.7b","article-title":"Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ","volume":"244","author":"Koch","year":"2006","journal-title":"Ann. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.humpath.2004.01.022","article-title":"Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability","volume":"35","author":"Prall","year":"2004","journal-title":"Hum. Pathol."},{"key":"ref_27","first-page":"4507","article-title":"The apoptosis inhibitor protein survivin induces tumor-specific CD8+ and CD4+ T cells in colorectal cancer patients","volume":"63","author":"Casati","year":"2003","journal-title":"Cancer Res."},{"key":"ref_28","first-page":"593","article-title":"Identification of neovasculature using nestin in colorectal cancer","volume":"30","author":"Teranishi","year":"2007","journal-title":"Int. J. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/bjd.12688","article-title":"Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: Systematic review and meta-analysis","volume":"170","author":"Pastushenko","year":"2014","journal-title":"Br. J. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s12105-011-0255-1","article-title":"Lack of correlation between microvascular density and pathological features and outcomes in sinonasal and oral mucosal melanomas","volume":"5","author":"Kerr","year":"2011","journal-title":"Head Neck Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jcpa.2012.02.001","article-title":"Lack of prognostic significance of angiogenesis in canine melanocytic tumours","volume":"147","author":"Cuitino","year":"2012","journal-title":"J. Comp. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"409","DOI":"10.3748\/wjg.v17.i4.409","article-title":"Nestin in gastrointestinal and colorectal cancers: Effects on cells and tumor angiogenesis","volume":"17","author":"Ishiwata","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1245\/s10434-010-0986-3","article-title":"2010 TNM staging system for cutaneous melanoma and beyond","volume":"17","author":"Gershenwald","year":"2010","journal-title":"Ann. Surg. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/4\/7876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:44:28Z","timestamp":1760215468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/4\/7876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,9]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,4]]}},"alternative-id":["ijms16047876"],"URL":"https:\/\/doi.org\/10.3390\/ijms16047876","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,9]]}}}