Publications Repository

Publications Repository

View item 
  •   Home
  • ICR Divisions
  • Other ICR Research
  • View item
  • Home
  • ICR Divisions
  • Other ICR Research
  • View item
JavaScript is disabled for your browser. Some features of this site may not work without it.

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

Thumbnail
View/Open
Accepted version (3.852Mb)
Date
2015-06-04
ICR Author
Erler, Janine Terra
Cox, Thomas
Bird, Demelza
Lang, Georgina
Author
Cox, TR
Rumney, RMH
Schoof, EM
Perryman, L
Hoye, AM
Agrawal, A
Bird, D
Ab Latif, N
Forrest, H
Evans, HR
Huggins, ID
Lang, G
Linding, R
Gartland, A
Erler, JT
Show allShow less
Type
Journal Article
Metadata
Show full item record
Abstract
Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia(1). Tumour-secreted proteins play a crucial role in these interactions(2-5) and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable(6). Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality(6,7). The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in patients with oestrogen-receptor negative breast cancer. Global quantitative analysis of the hypoxic secretome identified lysyl oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonize and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications.
URI
https://repository.icr.ac.uk/handle/internal/2252
DOI
https://doi.org/10.1038/nature14492
Collections
  • Other ICR Research
Language
eng
License start date
2015-06-04
Citation
NATURE, 2015, 522 pp. 106 - U279
Publisher
NATURE PUBLISHING GROUP

Browse

All of ICR repositoryICR DivisionsBy issue dateAuthorsTitlesPublication TypesThis collectionBy issue dateAuthorsTitlesPublication Types
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.