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

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 P1,2, Conte R1, Balza E3, Pietra G1,2, Mingari MC1,2, Carnemolla B1.
  • 1Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy.
  • 2Department of Experimental Medicine, University of Genoa, Genoa, Italy.
  • 3Laboratory of Cell Biology, IRCCS AOU San Martino-IST, Genoa, Italy.

 

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

PMID: 26460958

 

Key findings:

Angiogenesis is essential for tumor growth and survival, and metastasis [1]. Following the idea of starving the tumor, first proposed by J. Folkman more than 45 years ago, many anti-angiogenic drugs have been experimentally and clinically tested in the years [2, 3]. Several reports summarized the many anti-angiogenic biological drugs used in clinical practice to date. However now it is well known that resistance mechanisms to anti-angiogenic therapies exist and  they limit the long term benefit of these drugs [1-4]. In many malignant tumors, including metastatic melanoma, in addition to angiogenesis other forms of blood supply exist. One of these mechanisms is vascular mimicry (VM), in which cells of a highly aggressive malignant tumor can form vascular-like channels without implicating endothelial cells, thereby providing nutrients for tumor growth [5, 6]. It is emerging that, in the cure of solid tumors, the most effective therapies will entail targeting combinations of factors for drug delivery. Therefore novel markers of VM may be important targets for this purpose [5, 7-9].

Syndecan-1 is a cell surface heparan sulphate proteoglycan, and in some pathophysiological events as cancer its extracellular domain is proteolytically shed by metalloproteases and accumulated in the extracellular matrix (ECM) of tumor microenvironment. Stromal syndecan-1 is associated with elevated angiogenesis and poor prognosis in myeloma and in other cancers as epithelial ovarian cancer [10, 11].

Our studies clearly indicate, for the first time, that syndecan-1 is implicated in the process  of vascular mimicry in melanoma. We demonstrate by in vitro and in vivo experiments that OC-46F2, an anti-syndecan-1 fully human recombinant antibody [12], is able to inhibit the vascular mimicry of melanoma cells and vascular structure formation of endothelial cells. Recently, L19-IL2, an immunocytokine specific for the angiogenesis-associated B-fibronectin isoform, able to selectively accumulate on tumor neovasculature, has yielded encouraging results in a randomized phase II/III clinical trial in patients with metastatic melanoma [13, 14]. In this preclinical study, we show that OC-46F2 systemically administered in combination with L19-IL2, leads to a complete inhibition of melanoma growth until day 90 from tumor implantation in 71% of treated mice suggesting that the combined therapy could improve the therapeutic efficacy of both OC-46F2 and L19-IL2 administered as single agents. Besides human melanoma, VM has been observed in most malignant solid tumors including glioblastoma, ovarian, prostate and breast cancer [5], therefore blocking syndecan-1 activity by OC-46F2 antibody in combination therapy with L19-IL2 could result in potential novel therapeutic approaches for other different types of solid tumors.

 

 

fig1Figure 1: Schematic representation of vascular mimicry (VM) and neoangiogenesis of a very simplified tumor microenvironment of human melanoma xenograft model in NOD-SCID mouse. The anti-syndecan-1 human recombinant antibody (OC-46F2) recognizes both human and mouse syndecan-1 and it acts by suppressing maturation of vasculature structures originating from both tumoral (VM) and endothelial (neoangiogenesis) cells. In the right upper panel, the co-localization of syndecan-1 with human VM marker, CD144, and with the pericyte marker, SMA, is shown in immunofluorescence analysis on cryostat section of human melanoma induced in NOD-SCID mouse.

 

REFERENCES

  1. Weis SM, Cheresh DA (2011) Tumor angiogenesis: molecular pathways and therapeutic targets. Nature medicine 17: 1359-70.
  2. Folkman J (1971) Tumor angiogenesis: therapeutic implications. The New England journal of medicine 285: 1182-6.
  3. Dey N, De P, Brian LJ (2015) Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors. American journal of translational research 7: 1675-98.
  4. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273-86.
  5. Qiao L, Liang N, Zhang J, Xie J, Liu F, et al. (2015) Advanced research on vasculogenic mimicry in cancer. Journal of cellular and molecular medicine.
  6. Hendrix MJ, Seftor EA, Seftor RE, Chao JT, Chien DS, et al. (2016) Tumor cell vascular mimicry: Novel targeting opportunity in melanoma. Pharmacology & therapeutics.
  7. Abdollahi A, Folkman J (2010) Evading tumor evasion: current concepts and perspectives of anti-angiogenic cancer therapy. Drug Resist Updat 13: 16-28.
  8. Moserle L, Jimenez-Valerio G, Casanovas O (2014) Antiangiogenic therapies: going beyond their limits. Cancer Discov 4: 31-41.
  9. Helfrich I, Schadendorf D (2011) Blood vessel maturation, vascular phenotype and angiogenic potential in malignant melanoma: one step forward for overcoming anti-angiogenic drug resistance? Mol Oncol 5: 137-49.
  10. Palaiologou M, Delladetsima I, Tiniakos D (2014) CD138 (syndecan-1) expression in health and disease. Histology and histopathology 29: 177-89.
  11. Ramani VC, Purushothaman A, Stewart MD, Thompson CA, Vlodavsky I, et al. (2013) The heparanase/syndecan-1 axis in cancer: mechanisms and therapies. The FEBS journal 280: 2294-306.
  12. Orecchia P, Conte R, Balza E, Petretto A, Mauri P, et al. (2013) A novel human anti-syndecan-1 antibody inhibits vascular maturation and tumour growth in melanoma. Eur J Cancer 49: 2022-33.
  13. Kiefer JD, Neri D (2016) Immunocytokines and bispecific antibodies: two complementary strategies for the selective activation of immune cells at the tumor site. Immunological reviews 270: 178-92.
  14. Eigentler TK, Weide B, de Braud F, Spitaleri G, Romanini A, et al. (2011) A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 17: 7732-42.

 

Contact:

Barbara Carnemolla,  PhD

Laboratory  of Immunology

IRCCS San Martino-IST Istituto Nazionale per la

Ricerca sul Cancro

Largo Rosanna Benzi, 10

16132 Genoa, Italy

e-mail: barbaracarnemolla@libero.it

 

 

 

 

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