title: Targeting Syndecan-1, a molecule implicated in the process of vasculogenic mimicry, enhances the therapeutic efficacy of the L19-IL2 immunocytokine in human melanoma xenografts.
abstract: Anti-angiogenic therapy of solid tumors has until now failed to produce the long lasting clinical benefits desired, possibly due to the complexity of the neoangiogenic process. Indeed, a prominent role is played by "vasculogenic" or "vascular" mimicry (VM), a phenomenon in which aggressive cancer cells form an alternative microvascular circulation, independently of endothelial cell angiogenesis. In this study we observed, in melanoma patient cell lines having vasculogenic/stem-cell like phenotype and in melanoma tumors, the syndecan-1 co-expression with VM markers, such as CD144 and VEGFR-2. We show that melanoma cells lose their ability to form tubule-like structures in vitro after blocking syndecan-1 activity by the specific human recombinant antibody, OC-46F2. Moreover, in a human melanoma xenograft model, the combined therapy using OC-46F2 and L19-IL2, an immunocytokine specific for the tumor angiogenic-associated B-fibronectin isoform(B-FN), led to a complete inhibition of tumor growth until day 90 from tumor implantation in 71% of treated mice, with statistically significant differences compared to groups treated with OC-46F2 or L19-IL2 as monotherapy. Furthermore, in the tumors recovered from mice treated with OC-46F2 either as monotherapy or in combination with L19-IL2, we observed a dramatic decrease of vascular density and loss of VM structures. These findings indicate for the first time a role of syndecan-1 in melanoma VM and that targeting syndecan-1, together with B-FN, could be promising in improving the treatment of metastatic melanoma.
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.|Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Orecchia
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Conte
authors.affiliation: Laboratory of Cell Biology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.|Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.|Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.affiliation: Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Carnemolla
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000556:secondary; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018716:Molecular Mimicry; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D053668:Syndecan-1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099152:Cadherin 5
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D011993:Recombinant Fusion Proteins; D053668:Syndecan-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C554817:L19-IL2 immunocytokine; C508241:SDC1 protein, human; C000588866:KDR protein, human
keywords: angiogenesis; immunocytokine L19-IL2; melanoma combined therapy; scFv OC-46F2 anti Syndecan-1; vasculogenic/vascular mimicry