{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T11:12:38Z","timestamp":1772190758636,"version":"3.50.1"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,4,22]],"date-time":"2020-04-22T00:00:00Z","timestamp":1587513600000},"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>Therapy of multiple sclerosis (MS) with disease-modifying agents such as natalizumab or fingolimod has been associated with the development of cutaneous melanoma. Here we briefly revise literature data and report of a case of a 48-year old woman who developed a melanoma and several atypical naevi after sub sequential treatment with natalizumab (1 year) and fingolimod (7 years). By immunohistochemistry we observed the presence of T cells and leukocyte infiltration as well as of vascular endothelial growth factor (VEGF)-A expression in the patient melanoma biopsy. Then, we analyzed proliferation, migration and VEGF-A expression in three melanoma cell lines and found out that both natalizumab and fingolimod inhibited tumor cell proliferation but promoted or blocked cell migration depending on the cell line examined. VEGF-A secretion was augmented in one melanoma cell line only after fingolimod treatment. In conclusion, our in vitro data do not support the hypothesis of a direct action of natalizumab or fingolimod on melanoma progression but acting on the tumor microenvironment these treatments could indirectly favor melanoma evolution.<\/jats:p>","DOI":"10.3390\/ijms21082950","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T02:10:52Z","timestamp":1587607852000},"page":"2950","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Multiple Sclerosis Treatment and Melanoma Development"],"prefix":"10.3390","volume":"21","author":[{"given":"Maria Luigia","family":"Carbone","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1166-4593","authenticated-orcid":false,"given":"Pedro Miguel","family":"Lacal","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serena","family":"Messinese","sequence":"additional","affiliation":[{"name":"I Dermatology Department, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"De Giglio","sequence":"additional","affiliation":[{"name":"Medicine Department, Neurology Unit, San Filippo Neri Hospital, 00135 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Pozzilli","sequence":"additional","affiliation":[{"name":"Department of Human Neurosciences, Sant\u2019Andrea Hospital, MS Centre, Sapienza University, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Severino","family":"Persechino","sequence":"additional","affiliation":[{"name":"NESMOS Department, Dermatology Unit, Sant\u2019Andrea Hospital, Sapienza University, 00189 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cinzia","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"I Dermatology Department, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5991-8914","authenticated-orcid":false,"given":"Cristina Maria","family":"Failla","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianluca","family":"Pagnanelli","sequence":"additional","affiliation":[{"name":"I Dermatology Department, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/S0140-6736(16)32388-1","article-title":"Evolving concepts in the treatment of relapsing multiple sclerosis","volume":"389","author":"Comi","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/1756285617716002","article-title":"The role of natalizumab in the treatment of multiple sclerosis: Benefits and risks","volume":"10","author":"Singer","year":"2017","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.pharmthera.2017.11.001","article-title":"The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives","volume":"185","author":"Huwiler","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47281","DOI":"10.1074\/jbc.M306896200","article-title":"Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability","volume":"278","author":"Sanchez","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1073\/pnas.1014154108","article-title":"FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation","volume":"108","author":"Choi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10072-010-0427-x","article-title":"Association of melanoma and natalizumab therapy in the Italian MS population: A second case report","volume":"32","author":"Laroni","year":"2011","journal-title":"Neurol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1056\/NEJMoa044397","article-title":"AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis","volume":"354","author":"Polman","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1177\/1352458509347154","article-title":"Melanoma in multiple sclerosis treated with natalizumab: Causal association or coincidence?","volume":"15","author":"Bergamaschi","year":"2009","journal-title":"Mult. Scler."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1056\/NEJMc0706103","article-title":"Melanoma complicating treatment with natalizumab for multiple sclerosis","volume":"358","author":"Mullen","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1007\/s00415-009-5200-9","article-title":"Melanoma complicating treatment with natalizumab (Tysabri) for multiple sclerosis","volume":"256","author":"Ismail","year":"2009","journal-title":"J. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.annder.2009.03.018","article-title":"Natalizumab and atypical naevi: Comments on the pharmacovigilance note by J. L. Schmutz et al","volume":"136","author":"Yaldizli","year":"2009","journal-title":"Ann. Dermatol. Venereol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1177\/1352458510389629","article-title":"Diagnosis of melanoma under concomitant natalizumab therapy","volume":"17","author":"Vavricka","year":"2011","journal-title":"Mult. Scler."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1002\/cam4.1098","article-title":"Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)","volume":"6","author":"Sabol","year":"2017","journal-title":"Cancer Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1056\/NEJMoa0907839","article-title":"TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis","volume":"362","author":"Cohen","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1056\/NEJMoa0909494","article-title":"A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis","volume":"362","author":"Kappos","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1001\/archdermatol.2011.212","article-title":"Melanoma occurring during treatment with fingolimod for multiple sclerosis: A case report","volume":"147","author":"Kolm","year":"2011","journal-title":"Arch. Dermatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/ced.12770","article-title":"Superficial spreading malignant melanoma in a patient on fingolimod therapy for multiple sclerosis","volume":"41","author":"Haebich","year":"2015","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1212\/WNL.0000000000004293","article-title":"Five cases of malignant melanoma during fingolimod treatment in Dutch patients with MS","volume":"89","author":"Killestein","year":"2017","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"bcr2016217885","DOI":"10.1136\/bcr-2016-217885","article-title":"Fingolimod (Gilenya) and melanoma","volume":"2016","author":"Robinson","year":"2016","journal-title":"MBMJ Case Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1111\/ced.13066","article-title":"Fingolimod and melanoma risk: Is there sufficient evidence?","volume":"42","author":"Filoni","year":"2017","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.msard.2018.12.014","article-title":"Multiple sclerosis and cancer incidence: A Danish nationwide cohort study","volume":"28","author":"Norgaard","year":"2019","journal-title":"Mult. Scler. Relat. Disord"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.jaad.2018.10.052","article-title":"Melanoma subsequent to natalizumab exposure: A report from the RADAR (Research on Adverse Drug events and Reports) program","volume":"80","author":"Kelm","year":"2019","journal-title":"J. Am. Acad Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1001\/archdermatol.2010.243","article-title":"Evolution of Nevi during treatment with natalizumab","volume":"147","author":"Castela","year":"2011","journal-title":"Arch. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1001\/jamadermatol.2013.9411","article-title":"Risk for nevus transformation and melanoma proliferation and invasion during natalizumab treatment: Four years of dermoscopic follow-up with immunohistological studies and proliferation and invasion assay","volume":"150","author":"Pharaon","year":"2014","journal-title":"JAMA Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1158\/0008-5472.CAN-05-2001","article-title":"Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization","volume":"66","author":"LaMontagne","year":"2006","journal-title":"Cancer Res."},{"key":"ref_26","first-page":"1410","article-title":"Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models","volume":"62","author":"Azuma","year":"2002","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.6061\/clinics\/2013(07)21","article-title":"FTY720 induces apoptosis in B16F10-NEX2 murine melanoma cells, limits metastatic development in vivo, and modulates the immune system","volume":"68","author":"Pereira","year":"2013","journal-title":"Clinics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1292\/jvms.15-0193","article-title":"The therapeutic effects of SET\/I2PP2A inhibitors on canine melanoma","volume":"77","author":"Enjoji","year":"2015","journal-title":"J. Vet. Med. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1038\/onc.2017.2","article-title":"The protumorigenic potential of FTY720 by promoting extramedullary hematopoiesis and MDSC accumulation","volume":"36","author":"Li","year":"2017","journal-title":"Oncogene"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/0092-8674(94)90149-X","article-title":"Expression of the Integrin a4b1 on Melanoma Cells Can Inhibit the Invasive Stage of Metastasis Formation","volume":"77","author":"Qian","year":"1994","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/j.thromres.2014.02.020","article-title":"The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin","volume":"133","author":"Schlesinger","year":"2014","journal-title":"Thrombosis Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.imlet.2016.11.015","article-title":"In vitro VLA-4 blockade results in an impaired NK cell-mediated immune surveillance against melanoma","volume":"181","author":"Gandoglia","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1046\/j.1523-1747.2000.00199.x","article-title":"Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor","volume":"115","author":"Lacal","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.cell.2019.01.021","article-title":"VEGF in signaling and disease: Beyond discovery and development","volume":"176","author":"Apte","year":"2019","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s13046-017-0577-2","article-title":"The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells","volume":"36","author":"Atzori","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2950\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:23:29Z","timestamp":1760361809000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/8\/2950"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,22]]},"references-count":35,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["ijms21082950"],"URL":"https:\/\/doi.org\/10.3390\/ijms21082950","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,22]]}}}