LOX-Mediated Collagen Crosslinking Is Responsible for Fibrosis-Enhanced Metastasis
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Abstract
Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Identifying events involved in creating environments that promote metastatic colonization and growth are critical for the development of effective cancer therapies. Here, we show a critical role for lysyl oxidase (LOX) in establishing a milieu within fibrosing tissues that is favorable to growth of metastastic tumor cells. We show that LOX-dependent collagen crosslinking is involved in creating a growth-permissive fibrotic microenvironment capable of supporting metastatic growth by enhancing tumor cell persistence and survival. We show that therapeutic targeting of LOX abrogates not only the extent to which fibrosis manifests, but also prevents fibrosis-enhanced metastatic colonization. Finally, we show that the LOX-mediated collagen crosslinking directly increases tumor cell proliferation, enhancing metastatic colonization and growth manifesting in vivo as increased metastasis. This is the first time that crosslinking of collagen I has been shown to enhance metastatic growth. These findings provide an important link between ECM homeostasis, fibrosis, and cancer with important clinical implications for both the treatment of fibrotic disease and cancer. Cancer Res; 73(6); 1721–32. ©2012 AACR.
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- Authors
- Cox, T. R., Bird, D., Baker, A.-M., Barker, H. E., Ho, M. W.-Y., Lang, G., & Erler, J. T.
- Affiliations
- University of Copenhagen (DK)
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Erler, Janine T.
- Venue
- Cancer Research
- Published
- 2013-03-14
- Volume
- 73
- Issue
- 6
- Pages
- 1721-1732
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3672851
- OpenAlex
- W2135139969
- Cited by
- 571
- References
- 56
- Citations by year
- 2026: 51 · 2025: 34 · 2024: 34 · 2023: 48 · 2022: 46 · 2021: 47 · 2020: 45 · 2019: 44 · 2018: 56 · 2017: 47 · 2016: 50 · 2015: 25 · 2014: 30 · 2013: 13
- FWCI
- 21.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Cancer Research UK (C107/A10433, A10433)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Keywords
- lysyl oxidase, collagen cross-linking, type I collagen, tumor fibrosis, metastasis, tumor microenvironment, extracellular matrix, tumor cell proliferation, tumor cell survival, cancer therapy
- MeSH terms
- Cell Line, Collagen, Fibrosis, Fluorescent Antibody Technique, Humans, Lung Neoplasms, Protein-Lysine 6-Oxidase, Neoplasm Metastasis, Blotting, Western, Cell Proliferation
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