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Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2018 Jan 01; Vol. 110 (1). - Publication Year :
- 2018
-
Abstract
- Background: Cancer-associated fibroblasts (CAFs) are tumor-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.<br />Methods: CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4's role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9-15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided.<br />Results: Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69-7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65-0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%-79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%-64.0% decrease across different models, P ≤ .04).<br />Conclusions: These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.<br /> (© The Author 2017. Published by Oxford University Press.)
- Subjects :
- Actins analysis
Adenocarcinoma chemistry
Adenocarcinoma genetics
Adult
Aged
Aged, 80 and over
Animals
Cancer-Associated Fibroblasts chemistry
Cancer-Associated Fibroblasts physiology
Carcinoma, Non-Small-Cell Lung chemistry
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Squamous Cell chemistry
Carcinoma, Squamous Cell genetics
Cell Count
Cell Transdifferentiation drug effects
Cell Transdifferentiation genetics
Colorectal Neoplasms pathology
Disease Progression
Esophageal Neoplasms chemistry
Esophageal Neoplasms genetics
Female
Head and Neck Neoplasms chemistry
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms genetics
Humans
Lung Neoplasms chemistry
Lung Neoplasms genetics
Male
Mice
Middle Aged
Mouth Neoplasms pathology
Myofibroblasts chemistry
NADPH Oxidase 4
NADPH Oxidases analysis
NADPH Oxidases genetics
Neoplasm Transplantation
Oropharyngeal Neoplasms pathology
Phenotype
Pyrazoles therapeutic use
Pyrazolones
Pyridines therapeutic use
Pyridones
RNA Interference
Reactive Oxygen Species metabolism
Survival Rate
Up-Regulation
Adenocarcinoma drug therapy
Cancer-Associated Fibroblasts pathology
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Squamous Cell drug therapy
Colorectal Neoplasms chemistry
Esophageal Neoplasms drug therapy
Lung Neoplasms drug therapy
Mouth Neoplasms chemistry
Myofibroblasts pathology
NADPH Oxidases antagonists & inhibitors
Oropharyngeal Neoplasms chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 110
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 28922779
- Full Text :
- https://doi.org/10.1093/jnci/djx121