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

被引:55
作者
Itzhaki, Orit [1 ]
Greenberg, Eyal [1 ,2 ]
Shalmon, Bruria [4 ]
Kubi, Adva [1 ]
Treves, Avraham J. [3 ]
Shapira-Frommer, Ronnie [1 ]
Avivi, Camilla [4 ]
Ortenberg, Rona [1 ,2 ]
Ben-Ami, Eytan [1 ]
Schachter, Jacob [1 ]
Besser, Michal J. [1 ,2 ]
Markel, Gal [1 ,2 ,5 ]
机构
[1] Chaim Sheba Med Ctr, Ella Inst Melanoma, Ramat Gan, Israel
[2] Tel Aviv Univ, Sackler Fac Med, Dept Clin Microbiol & Immunol, IL-69978 Tel Aviv, Israel
[3] Chaim Sheba Med Ctr, Canc Res Ctr, Ramat Gan, Israel
[4] Chaim Sheba Med Ctr, Dept Pathol, Ramat Gan, Israel
[5] Chaim Sheba Med Ctr, Talpiot Med Leadership Program, Ramat Gan, Israel
来源
PLOS ONE | 2013年 / 8卷 / 02期
关键词
SCHIFF-POSITIVE PATTERNS; TUMOR-CELL PLASTICITY; CANCER STEM-CELLS; VE-CADHERIN; EMBRYONIC VASCULOGENESIS; PROGNOSTIC-SIGNIFICANCE; MALIGNANT-MELANOMA; EXPRESSION; DIFFERENTIATION; IMMUNOTHERAPY;
D O I
10.1371/journal.pone.0057160
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:11
相关论文
共 71 条
[1]  
Abramoff M.D., 2004, Biophotonics International, V11, P36
[2]  
Arganda-Carreras I, 2010, MICROSC RES TECH
[3]   Melanoma: A model for testing new agents in combination therapies [J].
Ascierto, Paolo A. ;
Streicher, Howard Z. ;
Sznol, Mario .
JOURNAL OF TRANSLATIONAL MEDICINE, 2010, 8
[4]   Nicotinamide Blocks Proliferation and Induces Apoptosis of Chronic Lymphocytic Leukemia Cells through Activation of the p53/miR-34a/SIRT1 Tumor Suppressor Network [J].
Audrito, Valentina ;
Vaisitti, Tiziana ;
Rossi, Davide ;
Gottardi, Daniela ;
D'Arena, Giovanni ;
Laurenti, Luca ;
Gaidano, Gianluca ;
Malavasi, Fabio ;
Deaglio, Silvia .
CANCER RESEARCH, 2011, 71 (13) :4473-4483
[5]   Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients [J].
Besser, Michal J. ;
Shapira-Frommer, Ronnie ;
Treves, Avraham J. ;
Zippel, Dov ;
Itzhaki, Orit ;
Hershkovitz, Liat ;
Levy, Daphna ;
Kubi, Adva ;
Hovav, Einat ;
Chermoshniuk, Natalia ;
Shalmon, Bruria ;
Hardan, Izhar ;
Catane, Raphael ;
Markel, Gal ;
Apter, Sara ;
Ben-Nun, Alon ;
Kuchuk, Iryna ;
Shimoni, Avichai ;
Nagler, Arnon ;
Schachter, Jacob .
CLINICAL CANCER RESEARCH, 2010, 16 (09) :2646-2655
[6]   Minimally Cultured or Selected Autologous Tumor-infiltrating Lymphocytes After a Lympho-depleting Chemotherapy Regimen in Metastatic Melanoma Patients [J].
Besser, Michal J. ;
Shapira-Frommer, Ronnie ;
Treves, Avraham J. ;
Zippel, Dov ;
Itzhaki, Orit ;
Schallmach, Ester ;
Kubi, Adva ;
Shalmon, Bruria ;
Hardan, Izhar ;
Catane, Raphael ;
Segal, Eran ;
Markel, Gal ;
Apter, Sara ;
Ben Nun, Alon ;
Kuchuk, Iryna ;
Shimoni, Avichai ;
Nagler, Arnon ;
Schachter, Jacob .
JOURNAL OF IMMUNOTHERAPY, 2009, 32 (04) :415-423
[7]   Molecular classification of cutaneous malignant melanoma by gene expression profiling [J].
Bittner, M ;
Meitzer, P ;
Chen, Y ;
Jiang, Y ;
Seftor, E ;
Hendrix, M ;
Radmacher, M ;
Simon, R ;
Yakhini, Z ;
Ben-Dor, A ;
Sampas, N ;
Dougherty, E ;
Wang, E ;
Marincola, F ;
Gooden, C ;
Lueders, J ;
Glatfelter, A ;
Pollock, P ;
Carpten, J ;
Gillanders, E ;
Leja, D ;
Dietrich, K ;
Beaudry, C ;
Berens, M ;
Alberts, D ;
Sondak, V ;
Hayward, N ;
Trent, J .
NATURE, 2000, 406 (6795) :536-540
[8]   EFFECT OF NICOTINAMIDE ON THE MICROREGIONAL HETEROGENEITY OF OXYGEN DELIVERY WITHIN A MURINE TUMOR [J].
CHAPLIN, DJ ;
HORSMAN, MR ;
TROTTER, MJ .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1990, 82 (08) :672-676
[9]   Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].
Chapman, Paul B. ;
Hauschild, Axel ;
Robert, Caroline ;
Haanen, John B. ;
Ascierto, Paolo ;
Larkin, James ;
Dummer, Reinhard ;
Garbe, Claus ;
Testori, Alessandro ;
Maio, Michele ;
Hogg, David ;
Lorigan, Paul ;
Lebbe, Celeste ;
Jouary, Thomas ;
Schadendorf, Dirk ;
Ribas, Antoni ;
O'Day, Steven J. ;
Sosman, Jeffrey A. ;
Kirkwood, John M. ;
Eggermont, Alexander M. M. ;
Dreno, Brigitte ;
Nolop, Keith ;
Li, Jiang ;
Nelson, Betty ;
Hou, Jeannie ;
Lee, Richard J. ;
Flaherty, Keith T. ;
McArthur, Grant A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516
[10]   ToppGene Suite for gene list enrichment analysis and candidate gene prioritization [J].
Chen, Jing ;
Bardes, Eric E. ;
Aronow, Bruce J. ;
Jegga, Anil G. .
NUCLEIC ACIDS RESEARCH, 2009, 37 :W305-W311