The DOI matches its Crossref record; 90 of the 91 references it cites were found in a registry or an index.
Oxidative stress promotes myofibroblast differentiation and tumour spreading
Open accessAbstract
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.
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“CAFs and ROS engage in two-way cross-talk: on the one hand, fibroblasts are targeted by ROS, particularly H2O2, which is able to convert them into active CAFs through the upregulation of HIF1α; on the other hand, CAFs are critical for the increase in ROS levels observed in cancer50,51.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [51]
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Hayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654
ROS in cancer therapy: the bright side of the moon
Perillo, B., Di Donato, M., Pezone, A., Di Zazzo, E., Giovannelli, P., Galasso, G., Castoria, G., & Migliaccio, A. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0384-2 · Cited by 2,176
Turning foes to friends: targeting cancer-associated fibroblasts
Chen, X., & Song, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0004-1 · Cited by 1,929
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705
Self-citationThe role of ROS in tumour development and progression
Cheung, E. C., & Vousden, K. H. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00435-0 · Cited by 1,663
Metadata
- Authors
- Toullec, A., Gerald, D., Despouy, G., Bourachot, B., Cardon, M., Lefort, S., Richardson, M., Rigaill, G., Parrini, M., Lucchesi, C., Bellanger, D., Stern, M., Dubois, T., Sastre‐Garau, X., Delattre, O., Vincent‐Salomon, A., & Mechta‐Grigoriou, F.
- Affiliations
- Inserm (FR)
- Institut Curie (FR)
- Corresponding author
- Mechta‐Grigoriou, Fatima
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2010-06-01
- Volume
- 2
- Issue
- 6
- Pages
- 211-230
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3377319
- OpenAlex
- W2107028932
- Cited by
- 339
- References
- 91
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 27 · 2023: 38 · 2022: 33 · 2021: 30 · 2020: 23 · 2019: 12 · 2018: 11 · 2017: 17 · 2016: 14 · 2015: 13 · 2014: 19 · 2013: 22 · 2012: 22
- FWCI
- 11.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Institut Curie
- Fondation de France
- Agence Nationale de la Recherche
- French National Institut of Cancer
- Association pour la Recherche contre le Cancer
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- oxidative stress, JunD, myofibroblast differentiation, tumour metastasis, reactive oxygen species, mammary carcinogenesis, stromal fibroblasts, HIF-1α, CXCL12, HER2-positive breast cancer, antioxidant therapy, tumor microenvironment, hypoxia
- MeSH terms
- Animals, Breast Neoplasms, Cell Differentiation, Cell Line, Female, Fibroblasts, Histocytochemistry, Humans, Immunohistochemistry, Locomotion, Microscopy, Microscopy, Fluorescence, Models, Biological, Neoplasm Metastasis, Proto-Oncogene Proteins, Mammary Neoplasms, Animal, Incidence, Survival Analysis, Proto-Oncogene Proteins c-jun, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Chemokine CXCL12
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