title: Lysyl Oxidase Is a Strong Determinant of Tumor Cell Colonization in Bone.
abstract: Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase whose primary function is to drive collagen crosslinking and extracellular matrix stiffness. LOX in colorectal cancer synergizes with hypoxia-inducible factor-1 (HIF-1) to promote tumor progression. Here we investigated whether LOX/HIF1 endows colorectal cancer cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from patients with colorectal cancer was associated with poor clinical outcome, irrespective of HIF-1 In addition, LOX was expressed by tumor cells in the bone marrow from colorectal cancer patients with bone metastases. In vivo experimental studies show that LOX overexpression in colorectal cancer cells or systemic delivery of the conditioned medium from LOX-overexpressing colorectal cancer cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1 Conversely, silencing or pharmacologic inhibition of LOX activity blocked dissemination of colorectal cancer cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of colorectal cancer cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in colorectal cancer cells also induced a robust production of IL6. In turn, both LOX and IL6 were acting in concert to promote RANKL-dependent osteoclast differentiation, thereby creating an imbalance between bone resorption and bone formation. Collectively, our findings show that LOX supports colorectal cancer cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL6 production by colorectal cancer cells impairs bone homeostasis. Cancer Res; 77(2); 268-78. ©2016 AACR.
authors.affiliation: INSERM, UMR1033, Lyon, France. philippe.clezardin@inserm.fr caroline.reynaud@inserm.fr.|University of Lyon, Villeurbanne, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Reynaud
authors.affiliation: INSERM, UMR1033, Lyon, France.|University of Lyon, Villeurbanne, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferreras
authors.affiliation: INSERM, UMR1033, Lyon, France.|University of Lyon, Villeurbanne, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Mauro
authors.affiliation: INSERM, UMR1033, Lyon, France.|University of Lyon, Villeurbanne, France.
authors.forename: Casina
authors.initials: C
authors.lastname: Kan
authors.affiliation: INSERM, UMR1033, Lyon, France.|University of Lyon, Villeurbanne, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Croset
authors.affiliation: INSERM, UMR1033, Lyon, France.|University of Lyon, Villeurbanne, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Bonnelye
authors.affiliation: CNRS, UMR5305, IBCP, Lyon, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Pez
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Clémence
authors.initials: C
authors.lastname: Thomas
authors.affiliation: CNRS, UMR5305, IBCP, Lyon, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Aimond
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Antoine E
authors.initials: AE
authors.lastname: Karnoub
authors.affiliation: INSERM, UMR1033, Lyon, France.|Department of Pathology, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Brevet
authors.affiliation: INSERM, UMR1033, Lyon, France. philippe.clezardin@inserm.fr caroline.reynaud@inserm.fr.|University of Lyon, Villeurbanne, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Clézardin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000556:secondary*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015850:Interleukin-6; D008249:Protein-Lysine 6-Oxidase