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Nat Commun. 2017 Feb 15;8:14206. doi: 10.1038/ncomms14206.

Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity.

Author information

1
Cancer Research UK Beatson Institute, Glasgow G611BD, UK.
2
Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B-3000, Belgium.
3
Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow G12 8LT, UK.
4
Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G611QH, UK.
5
School of Life Sciences, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
6
Centre for Health Technologies, University of Technology Sydney, Sydney, New South Wales 2007, Australia.
7
Department of Plasma Proteins, Sanquin Research, Amsterdam 1066 CX, The Netherlands.
8
Department of Pathology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
9
Laboratory of Angiogenesis and Vascular Metabolism, VIB Center for Cancer Biology, Vesalius Research Center, VIB, B-3000 Leuven, Belgium.

Abstract

The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.

PMID:
28198360
PMCID:
PMC5316871
DOI:
10.1038/ncomms14206
[Indexed for MEDLINE]
Free PMC Article

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