The involvement of Notch signaling in melanoma vasculogenic mimicry.

Notch signaling plays an important role in tumor angiogenesis. Recent studies suggest that Notch signaling also regulates the progression of primary melanomas toward an aggressive phenotype. The aim of this study was to investigate the involvement of Notch signaling pathway in organization of tumor cells into capillary-like structures (CLS), the phenomenon also known as vasculogenic mimicry (VM). Here, we show that Notch signaling cascade was constitutively active in melanoma cell lines we used. Blocking Notch signaling with the γ-secretase inhibitors, DAPT, dibenzazepine or Jagged1 neutralizing antibody resulted in stabilization of CLS indicating that Notch signaling pathway attenuates melanoma VM. We further studied this phenomenon on melanomas grafted in nude mice. Compared to control, VM channels in DAPT-treated grafted melanoma became larger and more branched. DAPT-treated melanomas also exhibited an up-regulation of MMP-2 and VEGFR1, both known as VM mediators. Moreover, we did not observe necrosis in VM channels areas of DAPT-treated melanomas. These findings indicate that VM regulated by Notch signaling may present a novel target in melanoma therapy.