Reynaud, C., Ferreras, L., Di Mauro, P. et al. (9 more authors) (2017) Lysyl oxidase is a strong determinant of tumor cell colonization in bone. Cancer Research, 77 (2). pp. 268-278. ISSN 0008-5472
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
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | ©2016 AACR. This is an author-produced version of a paper subsequently published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Animals; Blotting, Western; Bone Neoplasms; Bone and Bones; Cell Line, Tumor; Colorectal Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Heterografts; Humans; Immunohistochemistry; Interleukin-6; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Protein-Lysine 6-Oxidase; Real-Time Polymerase Chain Reaction |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Nov 2019 14:14 |
Last Modified: | 08 Nov 2019 14:24 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.can-15-2621 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152894 |