dc.contributor.author | Barker, HE | |
dc.contributor.author | Bird, D | |
dc.contributor.author | Lang, G | |
dc.contributor.author | Erler, JT | |
dc.date.accessioned | 2018-08-03T13:43:57Z | |
dc.date.issued | 2013-11-01 | |
dc.identifier | 11 | |
dc.identifier.citation | MOLECULAR CANCER RESEARCH, 2013, 11 pp. 1425 - 1436 | |
dc.identifier.issn | 1541-7786 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2263 | |
dc.identifier.eissn | 1557-3125 | |
dc.identifier.doi | 10.1158/1541-7786.MCR-13-0033-T | |
dc.description.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. | |
dc.format.extent | 1425 - 1436 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.title | Tumor-Secreted LOXL2 Activates Fibroblasts through FAK Signaling | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1158/1541-7786.MCR-13-0033-T | |
rioxxterms.licenseref.startdate | 2013-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | MOLECULAR CANCER RESEARCH | |
pubs.notes | affiliation: Erler, JT (Reprint Author), Univ Copenhagen, Biotech Res & Innovat Ctr, Ole Maaloes Vej 5, DK-2200 Copenhagen, Denmark. Barker, Holly E.; Bird, Demelza; Lang, Georgina; Erler, Janine T., Inst Canc Res, Sect Canc Biol, London SW3 6JB, England. Erler, Janine T., Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark. keywords-plus: FOCAL ADHESION KINASE; PROTEIN-TYROSINE KINASE; MUSCLE ACTIN EXPRESSION; LYSYL OXIDASE; STROMAL FIBROBLASTS; TRANSFORMING GROWTH-FACTOR-BETA-1; MYOFIBROBLAST DIFFERENTIATION; EXTRACELLULAR-MATRIX; COLORECTAL-CANCER; CELL-ADHESION research-areas: Oncology; Cell Biology web-of-science-categories: Oncology; Cell Biology author-email: [email protected] orcid-numbers: Erler, Janine/0000-0001-8675-6527 funding-acknowledgement: Association for International Cancer Research [09-0796]; Institute of Cancer Research; Cancer Research UK [C107/A10433/A11355]; Worldwide Cancer Research [09-0796] funding-text: This work was supported by the Association for International Cancer Research (#09-0796; to H.E. Barker), the Institute of Cancer Research (to H.E. Barker and J.T. Erler), and Cancer Research UK (#C107/A10433/A11355; to D. Bird, G. Lang, and J.T. Erler). number-of-cited-references: 49 times-cited: 32 usage-count-last-180-days: 0 usage-count-since-2013: 10 journal-iso: Mol. Cancer Res. doc-delivery-number: 258CE unique-id: ISI:000327435400012 oa: gold_or_bronze da: 2018-08-03 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy | |
pubs.volume | 11 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Targeted Therapy | |
dc.contributor.icrauthor | Barker, Holly | |
dc.contributor.icrauthor | Erler, Janine Terra | |