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

Paola Orecchia, Romana Conte, Enrica Balza, Gabriella Pietra, Maria Cristina Mingari, Barbara Carnemolla

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)37426-37442
Number of pages17
JournalOncotarget
Volume6
Issue number35
DOIs
Publication statusPublished - 2015

Fingerprint

Syndecan-1
Heterografts
Melanoma
Blood Vessels
Neoplasms
Fibronectins
Therapeutics
Interleukin-2
Protein Isoforms
Vascular Endothelial Growth Factor Receptor-2
L19-IL2 immunocytokine
Human Activities
Stem Cells
Endothelial Cells
Phenotype
Cell Line
Antibodies
Growth

Keywords

  • Angiogenesis
  • Immunocytokine L19-IL2
  • Melanoma combined therapy
  • scFv OC-46F2 anti Syndecan-1
  • vasculogenic/vascular mimicry

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Orecchia, Paola; Conte, Romana; Balza, Enrica; Pietra, Gabriella; Mingari, Maria Cristina; Carnemolla, Barbara.

In: Oncotarget, Vol. 6, No. 35, 2015, p. 37426-37442.

Research output: Contribution to journalArticle

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