Oxidative stress promotes myofibroblast differentiation and tumour spreading.
JunD regulates genes involved in antioxidant defence. We took advantage of the chronic oxidative stress resulting from junD deletion to examine the role of reactive oxygen species (ROS) in tumour development. In a model of mammary carcinogenesis, junD inactivation increased tumour incidence and revealed an associated reactive stroma. junD-inactivation in the stroma was sufficient to shorten tumour-free survival rate and enhance metastatic spread. ROS promoted conversion of fibroblasts into highly migrating myofibroblasts through accumulation of the hypoxia-inducible factor (HIF)-1alpha transcription factor and the CXCL12 chemokine. Accordingly, treatment with an antioxidant reduced the levels of HIF and CXCL12 and numerous myofibroblast features. CXCL12 accumulated in the stroma of HER2-human breast adenocarcinomas. Moreover, HER2 tumours exhibited a high proportion of myofibroblasts, which was significantly correlated to nodal metastases. Interestingly, this subset of tumours exhibited a significant nuclear exclusion of JunD and revealed an associated oxido-reduction signature, further demonstrating the relevance of our findings in human cancers. Collectively, our data uncover a new mechanism by which oxidative stress increases the migratory properties of stromal fibroblasts, which in turn potentiate tumour dissemination.
Toullec
Aurore
A
Laboratory of "Stress and Cancer", Inserm U830, Institut Curie, 75248 Paris Cedex 05, France.
Gerald
Damien
D
Despouy
Gilles
G
Bourachot
Brigitte
B
Cardon
Melissa
M
Lefort
Sylvain
S
Richardson
Marion
M
Rigaill
Guillem
G
Parrini
Maria-Carla
MC
Lucchesi
Carlo
C
Bellanger
Dorine
D
Stern
Marc-Henri
MH
Dubois
Thierry
T
Sastre-Garau
Xavier
X
Delattre
Olivier
O
Vincent-Salomon
Anne
A
Mechta-Grigoriou
Fatima
F
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000556:secondary*; D002454:Cell Differentiation; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D006651:Histocytochemistry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D015994:Incidence; D008124:Locomotion; D015674:Mammary Neoplasms, Animal / Q000473:pathology / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D008853:Microscopy; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009362:Neoplasm Metastasis / Q000473:pathology*; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species / Q000633:toxicity*; D016019:Survival Analysis
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; C528955:junD protein, mouse