INHIBITION OF "VASCULOGENIC MIMICRY", AN ALTERNATIVE PATHWAY OBSERVED IN HIGHLY AGGRESSIVE MELANOMA

Orit Itzhaki ¹ Eyal Greenberg ^1,2 Bruria Shalmon ⁴ Adva Kubi ¹ Avraham J. Treves ³ Ronnie Shapira-Frommer ¹ Camila Avivi ⁴ Rona Ortenberg ^1,2 Ben Ami Eitan ¹ Jacob Schachter ¹ Michal J. Besser ^1,2 Gal Markel ^1,2,5

¹Ella Institute of Melanoma, Sheba Medical Center, Ramat Gan
²Department of Clinical Microbiology and Immunology, Tel-Aviv Univercity, Sackler School of Medicine, Tel-Aviv
³Cancer Research Center, Sheba Medical Center, Ramat Gan
⁴Department of Pathology, Sheba Medical Center, Ramat Gan
⁵Talpiot Medical Leadership Program, Sheba Medical Center, Ramat Gan

Background

The presence of vascular channels is a precondition for tumor growth and metastasis. Highly plastic metastatic cell subpopulations closely interact with the tumor microenvironment to enable tumor progression. Vasculogenic mimicry (VM) formed by highly aggressive melanoma cells is a novel form of tumor microcirculation, which differs from classically described endothelium-dependent angiogenesis. The presence of VM predicts poor prognosis in melanoma patients. Abrogating this alternative vascularization pathway is of clinical importance, especially as several anti-angiogenic therapies, targeting endothelial cells, are largely ineffective in melanoma.

Aim

We tested the ability of nicotinamide, a derivate of vitamin B3, and IFNα, an immunomodulator with antiangiogenic effect, to inhibit VM formation in vitro.

Results

We could show the existence of VM channels in tumor tissues and primary cultures of advanced melanoma patients.

IFNα decreased the VM formation and invasiveness of treated cells in vitro. However, cell cycle analysis revealed a substantial induction of apoptosis, which might have caused VM abrogation in a non-specific manner.

Nicotinamide significantly inhibited the formation of VM structures in primary melanoma cultures and destroyed already formed ones in a dose-dependent manner, without considerably effecting apoptosis. Notably, VM formation capacity remained suppressed even one month after the complete withdrawal of nicotimamid from the cell culture media. Microarray analysis revealed a nicotinamide-driven down regulation of vascular endothelial cadherin (VE-Cadherin), a central player in VM formation. In addition, nicotinamide significantly inhibited the proliferation of melanoma cells, but increased their invasion capacity.

Conclusion

Nicotinamide effectively inhibits VM formation in primary melanoma cultures. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti-neoplastic effects in a variety of malignancies.