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Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling
Open accessPublished version of a preprint
Abstract
Cancer-associated fibroblasts enhance cancer progression when activated by tumor cells through mechanisms not yet fully understood. Blocking mammary tumor cell–derived lysyl oxidase-like 2 (LOXL2) significantly inhibited mammary tumor cell invasion and metastasis in transgenic and orthotopic mouse models. Here, we discovered that tumor-derived LOXL2 directly activated stromal fibroblasts in the tumor microenvironment. Genetic manipulation or antibody inhibition of LOXL2 in orthotopically grown mammary tumors reduced the expression of α-smooth muscle actin (α-SMA). Using a marker for reticular fibroblasts, it was determined that expression of α-SMA was localized to fibroblasts recruited from the host tissue. This marker also revealed that the matrix present in tumors with reduced levels of LOXL2 was more scattered compared with control tumors which exhibited matrices with dense, parallel alignments. Importantly, in vitro assays revealed that tumor-derived LOXL2 and a recombinant LOXL2 protein induced fibroblast branching on collagen matrices, as well as increased fibroblast-mediated collagen contraction and invasion of fibroblasts through extracellular matrix. Moreover, LOXL2 induced the expression of α-SMA in fibroblasts grown on collagen matrices. Mechanistically, it was determined that LOXL2 activated fibroblasts through integrin-mediated focal adhesion kinase activation. These results indicate that inhibition of LOXL2 in tumors not only reduces tumor cell invasion but also attenuates the activation of host cells in the tumor microenvironment. Implications: These findings reveal new insight into the mechanisms of fibroblast activation, a novel function of LOXL2, and further highlight the importance of generating LOXL2-targeted therapies for the prevention of tumor progression and metastasis. Mol Cancer Res; 11(11); 1425–36. ©2013 AACR.
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“Finally, CAFs secrete a plethora of soluble and ECM-associated factors, including cytokines, chemokines and growth factors that promote tumor growth and cancer cell dissemination40,240.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [240]
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Metadata
- Authors
- Barker, H. E., Bird, D., Lang, G., & Erler, J. T.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Erler, Janine T.
- Venue
- Molecular Cancer Research
- Published
- 2013-11-01
- Volume
- 11
- Issue
- 11
- Pages
- 1425-1436
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC3833835
- OpenAlex
- W2105524728
- Cited by
- 119
- References
- 52
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 15 · 2023: 8 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 13 · 2018: 9 · 2017: 10 · 2016: 11 · 2015: 8 · 2014: 8
- FWCI
- 4.82
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-10-01)
- Open access
- green
- europepmc.org
- Locations
- Molecular 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 (A11355, 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 › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- LOXL2, cancer-associated fibroblasts, fibroblast activation, focal adhesion kinase, integrin signaling, tumor microenvironment, mammary tumors, tumor invasion, metastasis, alpha-smooth muscle actin, collagen matrix, extracellular matrix remodeling
- MeSH terms
- Actins, Amino Acid Oxidoreductases, Animals, Cell Adhesion, Collagen, Extracellular Matrix, Female, Fibroblasts, Mammary Neoplasms, Experimental, Mice, Inbred C57BL, Neoplasm Invasiveness, Signal Transduction, Gene Expression Regulation, Neoplastic, 3T3 Cells, Cell Line, Tumor, Cell Proliferation, Mice, Focal Adhesion Kinase 1, Tumor Microenvironment
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