title: Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone.
abstract: Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1033, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France;
authors.forename: Raphael
authors.initials: R
authors.lastname: Leblanc
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Sue-Chin
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1037, Université de Toulouse III, Institut Claudius Regaud, Toulouse, France;
authors.forename: Marion
authors.initials: M
authors.lastname: David
authors.affiliation: EA4174, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France; and.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bordet
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Derek D
authors.initials: DD
authors.lastname: Norman
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Duane
authors.initials: D
authors.lastname: Miller
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1033, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France;
authors.forename: Debashish
authors.initials: D
authors.lastname: Sahay
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1033, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France;
authors.forename: Johnny
authors.initials: J
authors.lastname: Ribeiro
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1033, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Gabor J
authors.initials: GJ
authors.lastname: Tigyi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1033, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Peyruchaud
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology* / Q000473:pathology; D001859:Bone Neoplasms / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D001842:Bone and Bones / Q000276:immunology / Q000473:pathology; D001940:Breast / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000276:immunology*; D008246:Lysophospholipids / Q000276:immunology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D010727:Phosphoric Diester Hydrolases / Q000276:immunology*; D015539:Platelet Activation; D000099189:Lysophospholipase D
chemical_list: D039302:Integrin alphaVbeta3; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid