title: Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma.
abstract: Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin), which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin), which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. 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.
authors: Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, Israel.
authors: Orit
authors: O
authors: Itzhaki
authors: Eyal
authors: E
authors: Greenberg
authors: Bruria
authors: B
authors: Shalmon
authors: Adva
authors: A
authors: Kubi
authors: Avraham J
authors: AJ
authors: Treves
authors: Ronnie
authors: R
authors: Shapira-Frommer
authors: Camilla
authors: C
authors: Avivi
authors: Rona
authors: R
authors: Ortenberg
authors: Eytan
authors: E
authors: Ben-Ami
authors: Jacob
authors: J
authors: Schachter
authors: Michal J
authors: MJ
authors: Besser
authors: Gal
authors: G
authors: Markel
mesh_terms: D001808:Blood Vessels / Q000187:drug effects* / Q000254:growth & development; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000494:pharmacology*
chemical_list: D009536:Niacinamide