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The involvement of Notch signaling in melanoma vasculogenic mimicry

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Abstract

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.

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Abbreviations

VEGFR:

Vascular endothelial growth factor receptor

VM:

Vasculogenic mimicry

CLS:

Capillary-like structure

PAS:

Periodic Acid-Schiff reagent

EC:

Endothelial cells

MVD:

Microvascular density

ECM:

Extracellular matrix

PBS:

Phosphate buffer solution

RPMI 1640:

Roswell Park Memorial Institute 1640

Mel Kor:

Mel Cher and Mel P -melanoma cell lines, derived from surgical species of patients with disseminated melanoma

References

  1. Feige JJ (2010) Tumour angiogenesis: recent progress and remaining challenges. Bull Cancer 97(11):1305–1310

    PubMed  CAS  Google Scholar 

  2. Hiratsuka S (2011) Vasculogenesis, angiogenesis and special features of tumour blood vessels. Front Biosci 16:803–814

    Article  Google Scholar 

  3. Quesada AR, Medina MA, Munoz-Chapuli R, Ronce AL (2010) Do not say ever never more: the ins and outs of antiangiogenic therapies. Curr Pharm Des 16(35):3932–3957

    Article  PubMed  CAS  Google Scholar 

  4. Sharma PS, Sharma R, Tyagi T (2011) VEGF/VEGFR pathway inhibitors as anti-angiogenic agents: present and Future. Curr Cancer Drug Targets 11(5):624–633

    Article  PubMed  CAS  Google Scholar 

  5. Gerger A, LaBonte M, Lenz HL (2011) Molecular predictors of response to antiangiogenesis therapies. Cancer J 17(2):134–141

    Article  PubMed  CAS  Google Scholar 

  6. Fan YZ, Sun W (2010) Molecular regulation of vasculogenic mimicry in tumours and potential tumor-target therapy. World J Gastrointest Surg 2(4):117–124

    Article  PubMed  Google Scholar 

  7. Paulis YW, Soetekouw PM, Verheul HM (2010) Signaling pathways in vasculogenic mimicry. Biochem Biophys Acta 1806(1):18–28

    PubMed  CAS  Google Scholar 

  8. Schwanbeck R, Martini S, Bernoth K, Just U (2011) The Notch signalling pathway: molecular basis of cell content dependency. Eur J Cell Biol 90(6–7):572–581

    Article  PubMed  CAS  Google Scholar 

  9. Eiken HM, Adams RM (2010) Dynamics of endothelial cell behaviour in sprouting angiogenesis. Curr Opin Cell Biol 22(5):617–625

    Article  Google Scholar 

  10. Koch U, Radtke F (2010) Notch signaling in solid tumor. Curr Top Dev Biol 92:367–409

    Article  Google Scholar 

  11. Guo S, Liu M, Gouzalez-Perez RR (2011) Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochem Biophys Acta 1815(2):197–213

    PubMed  CAS  Google Scholar 

  12. Aster JC, Blacklow SC, Pear WS (2011) Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J Pathol 223(2):262–273

    Article  PubMed  CAS  Google Scholar 

  13. Sjolund J, Johanson M, Manna S, Norin C, Pietras A, Beckman S et al (2008) Suppression of renal cell carcinoma growth by inhibition of Notch signalling in vitro and in vivo. J Clin Invest 118(1):217–228

    Article  PubMed  Google Scholar 

  14. Massi D, Tarantini F, Franchi A, Paglierani M, Serio Di, Pellerito S et al (2006) Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma. Modern Pathol 19:246–254

    Article  CAS  Google Scholar 

  15. Jabobsson L, Bentley K, Gerhardt U (2009) VEGFRs and Notch: a dynamic collaboration in vascular patterning. Biochem Soc Trans 37(6):216–233

    Google Scholar 

  16. Cristofaro B, Emanueli C (2009) Possible novel targets for theraupetic angiogenesis. Curr Opin Pharmacol 9(2):102–108

    Article  PubMed  CAS  Google Scholar 

  17. Mikhailova IN, Lukashina MI, Baryshnikov AYu, Morozova LF, Kiselev CL, Georgiev GP (2005) Melanoma cell lines as the basis for antitumor vaccine preparation. Vest Ross Akad Med Nauk 7:37–40

    Google Scholar 

  18. Mikhailova IN, Kovalevsky DA, Morozova LF, Burova OS, Baryshnikov AYu, Bibilashvili RS (2008) Cancer/testis genes expression in human melanoma cell lines. Mel Res 18(5):303–313

    Article  Google Scholar 

  19. Vartanian A, Burova O, Stepanova E, Baryshnikov AYu, Lichinitser MR (2007) The involvement of apoptosis in melanoma vasculogenic mimicry. Mel Res 17:1–8

    Article  Google Scholar 

  20. Gridley T (2010) Notch signalling in the vasculature. Curr Top Dev Biol 92:277–309

    Article  PubMed  CAS  Google Scholar 

  21. Liu Z, Xiao M, Balint K, Smally K, Bradford P, Qiu R et al (2006) Notch signalling promotes primary melanoma progression by activating Mitogen-activated protein kinase/phosphatidylinosotol 3-kinase-Akt pathway and upregulate N-cadherin expression. Cancer Res 66:4182–4190

    Article  PubMed  CAS  Google Scholar 

  22. Kame T (2009) Novel insights into the differentiatial funcrions of Notch ligands in vascular formation. J Angiogeneisi Res 16:1–8

    Google Scholar 

  23. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D et al (2009) Preclinical profile of a potent γ-secretase inhibitor targeting Notch signalling with in vivo efficacy and pharmacodynamic properties. Cancer Res 68(19):7672–7680

    Article  Google Scholar 

  24. Hess AR, Seftor EA, Seftor RE, Hendrix MJ (2003) Phosphoinositide 3-kinase regulates membrane type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Cancer Res 63:4757–4762

    PubMed  CAS  Google Scholar 

  25. Vartanian A, Stepanova E, Grigorieva I, Solomko E, Baryshnikov A, Lichinitser M (2011) VEGFR1 and PKCalpha signalling control melanoma vasculogenic mimicry in a VEGFR2 kinase-independent manner. Mel Res 21(2):91–98

    Article  CAS  Google Scholar 

  26. Frank NY, Schatton T, Kim S, Zhan Q, Wilson BJ, Ma J (2011) VEGFR1 expressed by malignant melanoma-initiating cells is required for tumor growth. Cancer Res 71(4):1474–1485

    Article  PubMed  CAS  Google Scholar 

  27. Helfrich E, Schadendorf D (2011) Blood vessel maturation, vascular phenotype and angiogenic potential in malignant melanoma: one step forward for overcoming anti-angiogenic resistance? Mol Oncol 5:137–149

    Article  PubMed  CAS  Google Scholar 

  28. Ko JM, Verez NF (2010) Tsao H Pathways to melanoma. Semin Cutan Med Surg 29(4):210–217

    Article  PubMed  CAS  Google Scholar 

  29. Folberg R, Maniotis AJ (2004) Vasculogenic mimicry. Apmis 112:508–525

    Article  PubMed  Google Scholar 

  30. Yan M, Plowman GB (2007) Delta-like 4/Notch signalling and its theraupetic implications. Cancer Res 13(24):7243–7246

    CAS  Google Scholar 

  31. Hardy KM, Kirschmann DA, Seftor EA, Margaryan NV, Postovit LM, Hendrix MJ (2010) Regulation of the embryonic morphogen Nodal by Notch facilitates manifestation of the aggressive melanoma phenotype. Cancer Res 70(24):1034010350

    Article  Google Scholar 

  32. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F et al (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to I. Prudovsky for critical reading the MS, valuable comments and good advice

Conflict of interest

The authors state no conflict of interest.

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Authors and Affiliations

  1. N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoye shosse, 24, 115478, Moscow, Russia

    Amalia Vartanian, Galina Gatsina, Irina Grigorieva, Elico Solomko, Vladislav Dombrovsky, Anatoly Baryshnikov & Eugenia Stepanova

Authors
  1. Amalia Vartanian
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  2. Galina Gatsina
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  3. Irina Grigorieva
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  4. Elico Solomko
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  5. Vladislav Dombrovsky
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  6. Anatoly Baryshnikov
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  7. Eugenia Stepanova
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Corresponding author

Correspondence to Amalia Vartanian.

Additional information

This work was supported by an award to M.R. Lichinitser from the Foundation for Russian Ministry of Education and Science 02.512.11.2195.

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Vartanian, A., Gatsina, G., Grigorieva, I. et al. The involvement of Notch signaling in melanoma vasculogenic mimicry. Clin Exp Med 13, 201–209 (2013). https://doi.org/10.1007/s10238-012-0190-9

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  • DOI: https://doi.org/10.1007/s10238-012-0190-9

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