Research Papers:

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

Gabriela Schneider, Ewa Bryndza, Agata Poniewierska-Baran, Karol Serwin, Malwina Suszynska, Zachariah P. Sellers, Michael L. Merchant, Alagammai Kaliappan, Janina Ratajczak, Magda Kucia, Nichola C. Garbett and Mariusz Z. Ratajczak _

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Oncotarget. 2016; 7:69829-69843. https://doi.org/10.18632/oncotarget.12003

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Gabriela Schneider1, Ewa Bryndza1, Agata Poniewierska-Baran1,5, Karol Serwin4,5, Malwina Suszynska1, Zachariah P. Sellers1, Michael L. Merchant3, Alagammai Kaliappan2, Janina Ratajczak1, Magda Kucia1,4, Nichola C. Garbett2, Mariusz Z. Ratajczak1,4,5

1Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, KY, USA

2James Graham Brown Cancer Center, Department of Medicine, University of Louisville, KY, USA

3Kidney Disease Program, Department of Medicine, University of Louisville, KY, USA

4Department of Regenerative Medicine, Medical University of Warsaw, Poland

5Department of Physiology, Pomeranian Medical University, Szczecin, Poland

Correspondence to:

Mariusz Z. Ratajczak, email: [email protected]

Keywords: vitronectin, urokinase plasminogen activator receptor (uPAR), fibrinogen, cancer metastasis, chemotaxis

Received: July 18, 2016     Accepted: September 09, 2016     Published: September 13, 2016


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.

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