title: Evidence that vitronectin is a potent migration-enhancing factor for cancer cells chaperoned by fibrinogen: a novel view of the metastasis of cancer cells to low-fibrinogen lymphatics and body cavities.
abstract: Diluted (1%) plasma induces migration of malignant cell lines much more strongly than potent pro-metastatic factors. To characterize the factor(s) present in diluted plasma responsible for this phenomenon we performed i) heat inactivation, ii) dialysis, iii) proteinase K treatment, and iv) molecular size filtration studies. We found that this remarkable pro-migratory activity of diluted normal plasma is associated with a ~50-100-kD protein that interacts with GαI protein-coupled receptors and activates p42/44 MAPK and AKT signaling in target cells. Since this pro-migratory activity of 1% plasma decreases at higher plasma concentrations (> 20%), but is retained in serum, we hypothesized that fibrinogen may be involved as a chaperone of the protein(s). To identify the pro-migratory protein(s) present in diluted plasma and fibrinogen-depleted serum, we performed gel filtration and hydrophobic interaction chromatography followed by mass spectrometry analysis. We identified several putative protein candidates that were further tested in in vitro experiments. We found that this pro-migratory factor chaperoned by fibrinogen is vitronectin, which activates uPAR, and that this effect can be inhibited by fibrinogen. These results provide a novel mechanism for the metastasis of cancer cells to lymphatics and body cavities, in which the concentration of fibrinogen is low, and thus suggests that free vitronectin stimulates migration of tumor cells.
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schneider
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bryndza
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.|Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Poniewierska-Baran
authors.affiliation: Department of Regenerative Medicine Medical University of Warsaw, Poland.|Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Serwin
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.
authors.forename: Malwina
authors.initials: M
authors.lastname: Suszynska
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.
authors.forename: Zachariah P
authors.initials: ZP
authors.lastname: Sellers
authors.affiliation: Kidney Disease Program, Department of Medicine, University of Louisville, KY, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Merchant
authors.affiliation: James Graham Brown Cancer Center, Department of Medicine, University of Louisville, KY, USA.
authors.forename: Alagammai
authors.initials: A
authors.lastname: Kaliappan
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.
authors.forename: Janina
authors.initials: J
authors.lastname: Ratajczak
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.|Department of Regenerative Medicine Medical University of Warsaw, Poland.
authors.forename: Magda
authors.initials: M
authors.lastname: Kucia
authors.affiliation: James Graham Brown Cancer Center, Department of Medicine, University of Louisville, KY, USA.
authors.forename: Nichola C
authors.initials: NC
authors.lastname: Garbett
authors.affiliation: Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA.|Department of Regenerative Medicine Medical University of Warsaw, Poland.|Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Mariusz Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D001202:Ascitic Fluid / Q000502:physiology; D002465:Cell Movement; D002633:Chemotaxis; D005340:Fibrinogen / Q000502:physiology*; D006801:Humans; D008208:Lymphatic System / Q000502:physiology; D009362:Neoplasm Metastasis; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator / Q000502:physiology; D014407:Tumor Cells, Cultured; D019096:Vitronectin / Q000502:physiology*
chemical_list: D043562:Receptors, G-Protein-Coupled; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin; D005340:Fibrinogen
keywords: cancer metastasis; chemotaxis; fibrinogen; urokinase plasminogen activator receptor (uPAR); vitronectin