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Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis

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Abstract

Health beneficial effects of xanthohumol have been reported, and basic research provided evidence for anti-cancer effects. Furthermore, xanthohumol was shown to inhibit the migration of endothelial cells. Therefore, this study investigated the anti-metastatic potential of xanthohumol. MCF-7 breast cancer spheroids which are placed on lymphendothelial cells (LECs) induce “circular chemorepellent-induced defects” (CCIDs) in the LEC monolayer resembling gates for intravasating tumour bulks at an early step of lymph node colonisation. NF-κB reporter-, EROD-, SELE-, 12(S)-HETE- and adhesion assays were performed to investigate the anti-metastatic properties of xanthohumol. Western blot analyses were used to elucidate the mechanisms inhibiting CCID formation. Xanthohumol inhibited the activity of CYP, SELE and NF-kB and consequently, the formation of CCIDs at low micromolar concentrations. More specifically, xanthohumol affected ICAM-1 expression and adherence of MCF-7 cells to LECs, which is a prerequisite for CCID formation. Furthermore, markers of epithelial-to-mesenchymal transition (EMT) and of cell mobility such as paxillin, MCL2 and S100A4 were suppressed by xanthohumol. Xanthohumol attenuated tumour cell-mediated defects at the lymphendothelial barrier and inhibited EMT-like effects thereby providing a mechanistic explanation for the anti-intravasative/anti-metastatic properties of xanthohumol.

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Abbreviations

ALOX:

Lipoxygenase A

CCIDs:

Circular chemorepellent-induced defects

CYP:

Cytochrome P450

EMT:

Epithelial-to-mesenchymal transition

EROD:

Ethoxyresorufin-O-deethylase

HUVEC:

Human umbilical vein endothelial cell

ICAM-1:

Intercellular adhesion molecule 1

LEC:

Lymphendothelial cell

MCL2:

Myosin light chain 2

SELE:

Selectin E

12(S)-HETE:

12(S) Hydroxyeicosatetraenoic acid

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Acknowledgments

We wish to thank Toni Jäger for preparing the figures and to Prof. J. Ulrichova for kind gift of HUVEC cells. Further, Grant Nos. GACR (P505/11/1163) and ED0007/01/01 (both to M.S.) from the Centre of the Region Haná for Biotechnological and Agricultural Research, a grant of the Fellinger foundation (to G.K.), grants of the Herzfelder family foundation (to T.S., H.D., P.S. and M.G.), a grant of the “Hochschuljubilaeumsstiftung der Stadt Wien” grant number H-2498/2011 (to P.S.), a scholarship from the Austrian exchange service OeAD (to K.J.), and grants by the Austrian Science Fund, FWF, grant numbers P19598-B13 and P20905-B13 (to W.M.), S10704-B03 and S10704-B13 (to V.M.D.) and by the European Union, FP7 Health Research, project number HEALTH-F4-2008-202047 (to W.M.) are gratefully acknowledged.

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Authors and Affiliations

  1. Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Katharina Viola, Sabine Kopf, Nicole Kretschy, Mathias Teichmann, Caroline Vonach, Benedikt Giessrigl, Nicole Huttary, Ingrid Raab, Sigurd Krieger & Georg Krupitza

  2. Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 11, 783 71, Olomouc, Czech Republic

    Lucie Rarova & Miroslav Strnad

  3. Department for Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria

    Kanokwan Jarukamjorn & Walter Jäger

  4. Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand

    Kanokwan Jarukamjorn

  5. Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria

    Atanas G. Atanasov & Verena M. Dirsch

  6. Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettgasse 19, 1090, Vienna, Austria

    Rainer de Martin

  7. Department of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Philipp Saiko & Thomas Szekeres

  8. Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria

    Siegfried Knasmüller, Michael Grusch & Wolfgang Mikulits

  9. Institute of Medical Genetics, Medical University of Vienna, Währinger Strasse 10, 1090, Vienna, Austria

    Helmut Dolznig

Authors
  1. Katharina Viola
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  2. Sabine Kopf
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  3. Lucie Rarova
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  4. Kanokwan Jarukamjorn
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  5. Nicole Kretschy
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  6. Mathias Teichmann
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  7. Caroline Vonach
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  8. Atanas G. Atanasov
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  9. Benedikt Giessrigl
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  10. Nicole Huttary
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  15. Philipp Saiko
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  21. Helmut Dolznig
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  22. Wolfgang Mikulits
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  23. Georg Krupitza
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Corresponding author

Correspondence to Georg Krupitza.

Additional information

Katharina Viola and Sabine Kopf contributed equally to this work.

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Viola, K., Kopf, S., Rarova, L. et al. Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis. Arch Toxicol 87, 1301–1312 (2013). https://doi.org/10.1007/s00204-013-1028-2

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