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EMBO Rep. 2015 Oct;16(10):1394-408. doi: 10.15252/embr.201540107. Epub 2015 Aug 31.

Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis.

Author information

1
Tumour Cell Biology Laboratory, The Francis Crick Institute (formerly Cancer Research UK London Research Institute), London, UK Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark chris.madsen@bric.ku.dk erik.sahai@crick.ac.uk janine.erler@bric.ku.dk.
2
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
3
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
4
Department of Cell and Developmental Biology, University College London, London, UK London Centre for Nanotechnology, University College London, London, UK.
5
Tumour Cell Biology Laboratory, The Francis Crick Institute (formerly Cancer Research UK London Research Institute), London, UK chris.madsen@bric.ku.dk erik.sahai@crick.ac.uk janine.erler@bric.ku.dk.
6
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark chris.madsen@bric.ku.dk erik.sahai@crick.ac.uk janine.erler@bric.ku.dk.

Abstract

Cancer-associated fibroblasts (CAFs) interact with tumour cells and promote growth and metastasis. Here, we show that CAF activation is reversible: chronic hypoxia deactivates CAFs, resulting in the loss of contractile force, reduced remodelling of the surrounding extracellular matrix and, ultimately, impaired CAF-mediated cancer cell invasion. Hypoxia inhibits prolyl hydroxylase domain protein 2 (PHD2), leading to hypoxia-inducible factor (HIF)-1α stabilisation, reduced expression of αSMA and periostin, and reduced myosin II activity. Loss of PHD2 in CAFs phenocopies the effects of hypoxia, which can be prevented by simultaneous depletion of HIF-1α. Treatment with the PHD inhibitor DMOG in an orthotopic breast cancer model significantly decreases spontaneous metastases to the lungs and liver, associated with decreased tumour stiffness and fibroblast activation. PHD2 depletion in CAFs co-injected with tumour cells similarly prevents CAF-induced metastasis to lungs and liver. Our data argue that reversion of CAFs towards a less active state is possible and could have important clinical implications.

KEYWORDS:

PHD2; cancer‐associated fibroblasts; hypoxia; tumour invasion and metastasis; tumour stiffness

PMID:
26323721
PMCID:
PMC4662858
DOI:
10.15252/embr.201540107
[Indexed for MEDLINE]
Free PMC Article

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