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

Madsen, Chris D LU ; Pedersen, Jesper T; Venning, Freja A; Singh, Lukram Babloo; Moeendarbary, Emad; Charras, Guillaume; Cox, Thomas R; Sahai, Erik and Erler, Janine T (2015) In EMBO Reports 16(10). p.408-1394
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... (More)

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.

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keywords
Amino Acids, Dicarboxylic, Animals, Breast, Cell Adhesion Molecules, Cell Hypoxia, Cell Movement, Female, Fibroblasts, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Mammary Neoplasms, Experimental, Mice, Myosin Type II, Neoplasm Invasiveness, Neoplasm Metastasis, Organ Culture Techniques, Stromal Cells, Tumor Cells, Cultured, Journal Article, Research Support, Non-U.S. Gov't
in
EMBO Reports
volume
16
issue
10
pages
408 - 1394
publisher
Nature Publishing Group
external identifiers
  • scopus:84942825573
ISSN
1469-221X
DOI
10.15252/embr.201540107
language
English
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no
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1e07b700-8fda-440e-8f03-9481ddbd88cf
date added to LUP
2016-12-06 09:52:31
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2017-11-14 09:50:49
@article{1e07b700-8fda-440e-8f03-9481ddbd88cf,
  abstract     = {<p>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.</p>},
  author       = {Madsen, Chris D and Pedersen, Jesper T and Venning, Freja A and Singh, Lukram Babloo and Moeendarbary, Emad and Charras, Guillaume and Cox, Thomas R and Sahai, Erik and Erler, Janine T},
  issn         = {1469-221X},
  keyword      = {Amino Acids, Dicarboxylic,Animals,Breast,Cell Adhesion Molecules,Cell Hypoxia,Cell Movement,Female,Fibroblasts,Humans,Hypoxia-Inducible Factor 1, alpha Subunit,Hypoxia-Inducible Factor-Proline Dioxygenases,Mammary Neoplasms, Experimental,Mice,Myosin Type II,Neoplasm Invasiveness,Neoplasm Metastasis,Organ Culture Techniques,Stromal Cells,Tumor Cells, Cultured,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {10},
  pages        = {408--1394},
  publisher    = {Nature Publishing Group},
  series       = {EMBO Reports},
  title        = {Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis},
  url          = {http://dx.doi.org/10.15252/embr.201540107},
  volume       = {16},
  year         = {2015},
}