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Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling

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Date
2013-11
ICR Author
Erler, Janine Terra
Barker, Holly
Bird, Demelza
Lang, Georgina
Author
Barker, HE
Bird, D
Lang, G
Erler, JT
Type
Journal Article
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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 alpha-smooth muscle actin (alpha-SMA). Using a marker for reticular fibroblasts, it was determined that expression of alpha-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 alpha-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. (C) 2013 AACR.
URI
https://repository.icr.ac.uk/handle/internal/2263
DOI
https://doi.org/10.1158/1541-7786.MCR-13-0033-T
Collections
  • Cancer Biology
  • Radiotherapy and Imaging
Research team
Targeted Therapy
Language
eng
License start date
2013-11
Citation
MOLECULAR CANCER RESEARCH, 2013, 11 pp. 1425 - 1436
Publisher
AMER ASSOC CANCER RESEARCH

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