title: Targeting of CCL2-CCR2-Glycosaminoglycan Axis Using a CCL2 Decoy Protein Attenuates Metastasis through Inhibition of Tumor Cell Seeding.
abstract: The CCL2-CCR2 chemokine axis has an important role in cancer progression where it contributes to metastatic dissemination of several cancer types (e.g., colon, breast, prostate). Tumor cell-derived CCL2 was shown to promote the recruitment of CCR2(+)/Ly6C(hi) monocytes and to induce vascular permeability of CCR2(+) endothelial cells in the lungs. Here we describe a novel decoy protein consisting of a CCL2 mutant protein fused to human serum albumin (dnCCL2-HSA chimera) with enhanced binding affinity to glycosaminoglycans that was tested in vivo. The monocyte-mediated tumor cell transendothelial migration was strongly reduced upon unfused dnCCL2 mutant treatment in vitro. dnCCL2-HSA chimera had an extended serum half-life and thus a prolonged exposure in vivo compared with the dnCCL2 mutant. dnCCL2-HSA chimera bound to the lung vasculature but caused minimal alterations in the leukocyte recruitment to the lungs. However, dnCCL2-HSA chimera treatment strongly reduced both lung vascular permeability and tumor cell seeding. Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated upon dnCCL2-HSA chimera treatment. Tumor cell seeding to the lungs resulted in enhanced expression of a proteoglycan syndecan-4 by endothelial cells that correlated with accumulation of the dnCCL2-HSA chimera in the vicinity of tumor cells. These findings demonstrate that the CCL2-based decoy protein effectively binds to the activated endothelium in lungs and blocks tumor cell extravasation through inhibition of vascular permeability.
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, CH-8057 Zurich, Switzerland.
authors.forename: Marko
authors.initials: M
authors.lastname: Roblek
authors.affiliation: KF-University Graz, Graz Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Strutzmann
authors.affiliation: KF-University Graz, Graz Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Zankl
authors.affiliation: ProtAffin Biotechnologie AG, Graz Austria.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz Zentrum Munich für Gesundheit und Umwelt, Munich, Germany; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: VTU Technology GmbH, Grambach, Austria.
authors.forename: Aid
authors.initials: A
authors.lastname: Atlic
authors.affiliation: VTU Technology GmbH, Grambach, Austria.
authors.forename: Roland
authors.initials: R
authors.lastname: Weis
authors.affiliation: KF-University Graz, Graz Austria; ProtAffin Biotechnologie AG, Graz Austria; Antagonis Biotherapeutics, Graz Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kungl
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, CH-8057 Zurich, Switzerland. Electronic address: lborsig@access.uzh.ch.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D006025:Glycosaminoglycans; D054390:Receptors, CCR2; D011994:Recombinant Proteins; D053671:Syndecan-4