{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T09:07:49Z","timestamp":1783933669248,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale","award":["CUP I53D23000230006"],"award-info":[{"award-number":["CUP I53D23000230006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dermatopathology"],"abstract":"<jats:p>Background: Melanoma incidence is rising rapidly worldwide and stands out due to its high lethality. Despite advances in clinical treatment and in understanding melanoma-sensitive genes and molecular pathogenesis, a specific area of ongoing research is the connection between stress-related \u03b2-adrenergic receptors (ARs), hypoxia, and neovascularization in melanoma tumor progression. This exploratory study aimed to investigate the expression of \u03b23-AR, HIF-1\u03b1, and CD31 in several cellular subsets of atypical melanocytic lesions and their interplay in promoting melanoma malignancy. Methods: Twenty-seven patients with melanocytic lesions at different stages that were surgically removed were retrospectively selected; clinical-pathological and dermoscopic data were collected. Results: Immunohistochemical and digital evaluation revealed a significant upregulation of \u03b23-AR in malignant melanoma melanocytes and in macrophages from invasive &gt;pT1a melanomas compared to dysplastic nevi. Increased HIF-1\u03b1 expression in malignant melanocytes and CD31 expression levels in &gt;pT1a melanomas were observed. Ulcerated lesions exhibited a higher percentage of \u03b23-AR, HIF-1\u03b1, and CD31 expression. Pearson correlation analysis revealed positive associations among these markers in human malignant melanoma, suggesting a potential relationship between adrenergic signaling, hypoxia, and tumor vascularization. Conclusions: These exploratory findings suggest that \u03b23-AR, HIF-1\u03b1, and CD31 may represent interconnected components of the melanoma microenvironment. Unraveling these interactions in larger, independent cohorts and functional studies may provide additional insights into melanoma biology and help define their potential translational relevance.<\/jats:p>","DOI":"10.3390\/dermatopathology13030031","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:15:04Z","timestamp":1783091704000},"page":"31","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring \u03b23-Adrenergic Receptor, HIF-1\u03b1, and CD31 Interplay in the Microenvironment of Atypical Melanocytic Lesions"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8154-3730","authenticated-orcid":false,"given":"Eugenia","family":"Belcastro","sequence":"first","affiliation":[{"name":"Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-7980","authenticated-orcid":false,"given":"Giuseppe Nicol\u00f2","family":"Fanelli","sequence":"additional","affiliation":[{"name":"Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Oncology, Pisa University Hospital, 56126 Pisa, Italy"},{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Fidanzi","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Pisa University Hospital, 56126 Pisa, Italy"},{"name":"Melanoma and Skin Cancer Unit AVNO (Area Vasta Nord Ovest) Tuscany, Carrara Hospital, 54033 Carrara, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desir\u00e8e","family":"Fischetti","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7783-0262","authenticated-orcid":false,"given":"Riccardo","family":"Morganti","sequence":"additional","affiliation":[{"name":"Statistics Unit, Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"De Ieso","sequence":"additional","affiliation":[{"name":"Department of Oncology, Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5310-9147","authenticated-orcid":false,"given":"Luca","family":"Filippi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"},{"name":"Neonatal Intensive Care Unit, Meyer Children\u2019s Hospital IRCCS, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8195-9445","authenticated-orcid":false,"given":"Antonio Giuseppe","family":"Naccarato","sequence":"additional","affiliation":[{"name":"Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Oncology, Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-0141","authenticated-orcid":false,"given":"Marco","family":"Romanelli","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Pisa University Hospital, 56126 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4862-0845","authenticated-orcid":false,"given":"Cristian","family":"Scatena","sequence":"additional","affiliation":[{"name":"Division of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy"},{"name":"Department of Oncology, Pisa University Hospital, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Janowska","sequence":"additional","affiliation":[{"name":"Unit of Dermatology, Pisa University Hospital, 56126 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrc.2017.43","article-title":"Melanoma: A global perspective","volume":"17","author":"Ossio","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1097\/CEJ.0000000000000747","article-title":"Epidemiology of melanoma: The importance of correctly reporting to the cancer registries","volume":"31","author":"Fidanzi","year":"2022","journal-title":"Eur. J. Cancer Prev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1111\/jdv.19221","article-title":"Dermoscopy of melanoma according to different body sites: Head and neck, trunk, limbs, nail, mucosal and acral","volume":"37","author":"Longo","year":"2023","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1001\/archderm.140.12.1485","article-title":"Vascular structures in skin tumors: A dermoscopy study","volume":"140","author":"Argenziano","year":"2004","journal-title":"Arch. Dermatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1038\/jid.2013.115","article-title":"Hypoxia contributes to melanoma heterogeneity by triggering HIF1alpha-dependent phenotype switching","volume":"133","author":"Widmer","year":"2013","journal-title":"J. Investig. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Scatena, C., Murtas, D., and Tomei, S. (2021). Cutaneous Melanoma Classification: The Importance of High-Throughput Genomic Technologies. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.635488"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00428-023-03720-5","article-title":"Shedding light on PRAME expression in dysplastic nevi: A cohort study","volume":"485","author":"Innocenti","year":"2024","journal-title":"Virchows Arch."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Massone, C., Hofman-Wellenhof, R., Chiodi, S., and Sola, S. (2021). Dermoscopic Criteria, Histopathological Correlates and Genetic Findings of Thin Melanoma on Non-Volar Skin. Genes, 12.","DOI":"10.3390\/genes12081288"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1007\/s12325-023-02555-5","article-title":"Management of Advanced Invasive Melanoma: New Strategies","volume":"40","author":"Villani","year":"2023","journal-title":"Adv. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Janowska, A., Iannone, M., Fidanzi, C., Romanelli, M., Filippi, L., Del Re, M., Martins, M., and Dini, V. (2022). The Genetic Basis of Dormancy and Awakening in Cutaneous Metastatic Melanoma. Cancers, 14.","DOI":"10.3390\/cancers14092104"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1158\/1078-0432.CCR-11-0641","article-title":"Molecular pathways: Beta-adrenergic signaling in cancer","volume":"18","author":"Cole","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/labinvest.2012.175","article-title":"\u03b2-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines","volume":"93","author":"Moretti","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc3978","article-title":"Sympathetic nervous system regulation of the tumour microenvironment","volume":"15","author":"Cole","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.18632\/oncotarget.2652","article-title":"Norepinephrine promotes tumor microenvironment reactivity through \u03b23-adrenoreceptors during melanoma progression","volume":"6","author":"Calvani","year":"2015","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s00109-013-1073-6","article-title":"Functional involvement of \u03b23-adrenergic receptors in melanoma growth and vascularization","volume":"91","author":"Casini","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s00210-014-0969-1","article-title":"\u03b23-adrenergic receptor activity modulates melanoma cell proliferation and survival through nitric oxide signaling","volume":"387","author":"Fornaciari","year":"2014","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.bbi.2008.10.005","article-title":"Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: Implications for stress-related enhancement of tumor progression","volume":"23","author":"Yang","year":"2009","journal-title":"Brain Behav. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/j.1582-4934.2011.01375.x","article-title":"Role of endothelial nitric oxide synthase (eNOS) in chronic stress-promoted tumour growth","volume":"16","author":"Barbieri","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1097\/CMR.0000000000000393","article-title":"A prospective multicenter cohort study of cutaneous melanoma: Clinical staging and potential associations with HIF-1alpha and VEGF expressions","volume":"27","author":"Nagore","year":"2017","journal-title":"Melanoma Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Amato, R., Pisani, F., Laudadio, E., Cammalleri, M., Lucchesi, M., Marracci, S., Filippi, L., Galeazzi, R., Svelto, M., and Dal Monte, M. (2022). HIF-1-Dependent Induction of \u03b23 Adrenoceptor: Evidence from the Mouse Retina. Cells, 11.","DOI":"10.3390\/cells11081271"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1111\/bph.14552","article-title":"\u03b2-Adrenoceptors as drug targets in melanoma: Novel preclinical evidence for a role of \u03b23-adrenoceptors","volume":"176","author":"Calvani","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/j.1365-2559.2005.02193.x","article-title":"Microvessel density for melanoma prognosis","volume":"47","author":"Depasquale","year":"2005","journal-title":"Histopathology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1245\/s10434-018-6513-7","article-title":"Melanoma Staging: American Joint Committee on Cancer (AJCC) 8th Edition and Beyond","volume":"25","author":"Gershenwald","year":"2018","journal-title":"Ann. Surg. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Schena, G., and Caplan, M.J. (2019). Everything You Always Wanted to Know about \u03b23-AR * (* But Were Afraid to Ask). Cells, 8.","DOI":"10.3390\/cells8040357"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Calvani, M., Dabraio, A., Bruno, G., De Gregorio, V., Coronnello, M., Bogani, C., Ciullini, S., Marca, G., Vignoli, M., and Chiarugi, P. (2020). \u03b23-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124210"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/s43018-024-00794-1","article-title":"Determinants of resistance and response to melanoma therapy","volume":"5","author":"Robertson","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12964-025-02173-4","article-title":"Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: From mechanisms to therapeutic opportunities","volume":"23","author":"Bellazzo","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kharouf, N., Flanagan, T.W., Hassan, S.Y., Shalaby, H., Khabaz, M., Hassan, S.L., Megahed, M., Haikel, Y., Santourlidis, S., and Hassan, M. (2023). Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment. Cancers, 15.","DOI":"10.3390\/cancers15123147"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.canlet.2019.05.021","article-title":"Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints","volume":"458","author":"Lequeux","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4725","DOI":"10.1038\/s41388-021-01846-x","article-title":"Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy","volume":"40","author":"Lequeux","year":"2021","journal-title":"Oncogene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11481-019-09876-9","article-title":"The Role of \u03b2-Blockers in Melanoma","volume":"15","author":"Geppetti","year":"2020","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cassano, R., Cuconato, M., Calviello, G., Serini, S., and Trombino, S. (2021). Recent Advances in Nanotechnology for the Treatment of Melanoma. Molecules, 26.","DOI":"10.3390\/molecules26040785"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102379","DOI":"10.1016\/j.nano.2021.102379","article-title":"Fluorescent nanocarriers targeting VCAM-1 for early detection of senescent endothelial cells","volume":"34","author":"Belcastro","year":"2021","journal-title":"Nanomedicine"}],"container-title":["Dermatopathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2296-3529\/13\/3\/31\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:32:30Z","timestamp":1783931550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2296-3529\/13\/3\/31"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["dermatopathology13030031"],"URL":"https:\/\/doi.org\/10.3390\/dermatopathology13030031","relation":{},"ISSN":["2296-3529"],"issn-type":[{"value":"2296-3529","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,3]]}}}