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

Oncotarget. 2015 Nov 10;6(35):37426-42. doi: 10.18632/oncotarget.6055.

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.

Keywords: angiogenesis; immunocytokine L19-IL2; melanoma combined therapy; scFv OC-46F2 anti Syndecan-1; vasculogenic/vascular mimicry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, CD / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Coculture Techniques
  • Female
  • Humans
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Melanoma / blood supply
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / metabolism
  • Melanoma / secondary
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Mimicry*
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic / drug effects
  • Phenotype
  • Recombinant Fusion Proteins / pharmacology*
  • Skin Neoplasms / blood supply
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Syndecan-1 / antagonists & inhibitors*
  • Syndecan-1 / immunology
  • Syndecan-1 / metabolism
  • Time Factors
  • Tumor Burden
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antibodies, Monoclonal
  • Antigens, CD
  • Cadherins
  • L19-IL2 immunocytokine
  • Recombinant Fusion Proteins
  • SDC1 protein, human
  • Syndecan-1
  • cadherin 5
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2