Lysyl oxidase is a strong determinant of tumor cell colonization in bone. Short Title: LOX triggers 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 (CRC) synergizes with hypoxia-inducible factor-1 (HIF-1 to promote tumor progression. Here we investigated whether LOX/HIF1 endows CRC cells with full competence for aggressive colonization in bone. We show that a high LOX expression in primary tumors from CRC patients was associated with poor clinical outcome, irrespective of HIF-1. Additionally, LOX was expressed by tumor cells in the bone marrow from CRC patients with bone metastases. In vivo experimental studies show that LOX overexpression in CRC cells or systemic delivery of the conditioned medium from LOX-overexpressing CRC cells promoted tumor cell dissemination in the bone marrow and enhanced osteolytic lesion formation, irrespective of HIF-1. Conversely, silencing or pharmacological inhibition of LOX activity blocked dissemination of CRC cells in the bone marrow and tumor-driven osteolytic lesion formation. In vitro, tumor-secreted LOX supported the attachment and survival of CRC cells to and in the bone matrix, and inhibited osteoblast differentiation. LOX overexpression in CRC cells also induced a robust production of IL-6. In turn, both LOX and IL-6 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 CRC cell dissemination in the bone marrow and they reveal a novel mechanism through which LOX-driven IL-6 production by CRC cells impairs bone homeostasis.
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Cancer Research, American Association for Cancer Research, 2016, [Epub ahead of print]
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Caroline Reynaud, Laura Ferreras, Paola Mauro, Casina Kan, Martine Croset, et al.. Lysyl oxidase is a strong determinant of tumor cell colonization in bone. Short Title: LOX triggers tumor cell colonization in bone. Cancer Research, American Association for Cancer Research, 2016, [Epub ahead of print]. 〈inserm-01404358〉

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