title: Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis.
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.
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Viola
authors.forename: Sabine
authors.initials: S
authors.lastname: Kopf
authors.forename: Lucie
authors.initials: L
authors.lastname: Rarova
authors.forename: Kanokwan
authors.initials: K
authors.lastname: Jarukamjorn
authors.forename: Nicole
authors.initials: N
authors.lastname: Kretschy
authors.forename: Mathias
authors.initials: M
authors.lastname: Teichmann
authors.forename: Caroline
authors.initials: C
authors.lastname: Vonach
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.forename: Benedikt
authors.initials: B
authors.lastname: Giessrigl
authors.forename: Nicole
authors.initials: N
authors.lastname: Huttary
authors.forename: Ingrid
authors.initials: I
authors.lastname: Raab
authors.forename: Sigurd
authors.initials: S
authors.lastname: Krieger
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Rainer
authors.initials: R
authors.lastname: de Martin
authors.forename: Philipp
authors.initials: P
authors.lastname: Saiko
authors.forename: Thomas
authors.initials: T
authors.lastname: Szekeres
authors.forename: Siegfried
authors.initials: S
authors.lastname: Knasmüller
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Helmut
authors.initials: H
authors.lastname: Dolznig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D018920:Coculture Techniques; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011427:Propiophenones / Q000494:pharmacology*; D018874:Spheroids, Cellular; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D019040:E-Selectin; D005419:Flavonoids; C573420:ICAM1 protein, human; D016328:NF-kappa B; D011427:Propiophenones; C546936:SELE protein, human; D018799:Intercellular Adhesion Molecule-1; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C104536:xanthohumol