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Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma

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 targeti...

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Autores principales: Itzhaki, Orit, Greenberg, Eyal, Shalmon, Bruria, Kubi, Adva, Treves, Avraham J., Shapira-Frommer, Ronnie, Avivi, Camilla, Ortenberg, Rona, Ben-Ami, Eytan, Schachter, Jacob, Besser, Michal J., Markel, Gal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581583/
https://www.ncbi.nlm.nih.gov/pubmed/23451174
http://dx.doi.org/10.1371/journal.pone.0057160
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author Itzhaki, Orit
Greenberg, Eyal
Shalmon, Bruria
Kubi, Adva
Treves, Avraham J.
Shapira-Frommer, Ronnie
Avivi, Camilla
Ortenberg, Rona
Ben-Ami, Eytan
Schachter, Jacob
Besser, Michal J.
Markel, Gal
author_facet Itzhaki, Orit
Greenberg, Eyal
Shalmon, Bruria
Kubi, Adva
Treves, Avraham J.
Shapira-Frommer, Ronnie
Avivi, Camilla
Ortenberg, Rona
Ben-Ami, Eytan
Schachter, Jacob
Besser, Michal J.
Markel, Gal
author_sort Itzhaki, Orit
collection PubMed
description 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.
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spelling pubmed-35815832013-02-28 Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma Itzhaki, Orit Greenberg, Eyal Shalmon, Bruria Kubi, Adva Treves, Avraham J. Shapira-Frommer, Ronnie Avivi, Camilla Ortenberg, Rona Ben-Ami, Eytan Schachter, Jacob Besser, Michal J. Markel, Gal PLoS One Research Article 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. Public Library of Science 2013-02-25 /pmc/articles/PMC3581583/ /pubmed/23451174 http://dx.doi.org/10.1371/journal.pone.0057160 Text en © 2013 Itzhaki et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Itzhaki, Orit
Greenberg, Eyal
Shalmon, Bruria
Kubi, Adva
Treves, Avraham J.
Shapira-Frommer, Ronnie
Avivi, Camilla
Ortenberg, Rona
Ben-Ami, Eytan
Schachter, Jacob
Besser, Michal J.
Markel, Gal
Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title_full Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title_fullStr Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title_full_unstemmed Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title_short Nicotinamide Inhibits Vasculogenic Mimicry, an Alternative Vascularization Pathway Observed in Highly Aggressive Melanoma
title_sort nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581583/
https://www.ncbi.nlm.nih.gov/pubmed/23451174
http://dx.doi.org/10.1371/journal.pone.0057160
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