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Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4

Hanley, Christopher, Mellone, Massimiliano, Ford, Kirsty, Thirdborough, Stephen, Mellows, Toby, Frampton, Steven, James, Harden, Elena, Thomas, Gareth, Smith, David M., Szyndralewiez, Cedric, Bullock, Marc, Noble, Fergus, Moutasim, Karwan, King, Emma, Vijayanand, Pandurangan, Mirnezami, Alex H., Underwood, Tim J., Ottensmeier, Christian H. and Thomas, Gareth (2018) Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4 Journal of the National Cancer Institute, 110, (1) (doi:10.1093/jnci/djx121).

Record type: Article

Abstract

Background: Cancer-associated fibroblasts (CAFs) are tumour-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods: CAF accumulation and prognostic significance in head & neck cancer (oral and oropharyngeal), and colorectal cancer was analysed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by PCR, Western blotting, immunofluorescence and functional assays. RNA-Sequencing/bioinformatics and immunohistochemistry was used to analyse NAD(P)H Oxidase-4 (NOX4) expression in different human tumours. NOX4’s role in CAF-mediated tumour progression was assessed in vitro –using CAFs from multiple tissues in Transwell and organotypic culture assays; and in vivo ¬–using xenograft and isograft tumour models. All statistical tests were two-sided. Results: We found myofibroblastic-CAF correlated significantly with poor survival in multiple solid cancers (HRs=1.7-7.3;p≤0.014). Fibroblast-to-myofibroblast transdifferentiation was shown to be dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. NOX4 expression was significantly upregulated in multiple human cancers (p<0.0001), strongly correlating with myofibroblastic-CAFs (r=0.647-0.913; adj. p<1x10-24). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex-vivo (54% decrease in α-SMA, p<0.01); prevent myofibroblastic-CAF accumulation in vivo (53-79% decrease in α-SMA across different models; p≤0.02) and slow tumour growth (30-64% decrease across different models, p≤0.04).

Text Hanley et al., 2017 - Accepted Manuscript
Restricted to Repository staff only until 18 May 2018.
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 18 May 2017
e-pub ahead of print date: 3 August 2017
Published date: 1 January 2018

Identifiers

Local EPrints ID: 412569
URI: http://eprints.soton.ac.uk/id/eprint/412569
ISSN: 0027-8874
PURE UUID: c41dffc3-82ca-4597-a41e-51fce157948c
ORCID for Christopher Hanley: ORCID iD orcid.org/0000-0003-3816-7220
ORCID for Tim J. Underwood: ORCID iD orcid.org/0000-0001-9455-2188

Catalogue record

Date deposited: 21 Jul 2017 16:31
Last modified: 19 Oct 2017 16:31

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Contributors

Author: Christopher Hanley ORCID iD
Author: Massimiliano Mellone
Author: Kirsty Ford
Author: Toby Mellows
Author: Steven, James Frampton
Author: Elena Harden
Author: Gareth Thomas
Author: David M. Smith
Author: Cedric Szyndralewiez
Author: Marc Bullock
Author: Fergus Noble
Author: Karwan Moutasim
Author: Emma King
Author: Pandurangan Vijayanand
Author: Gareth Thomas

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