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Title: Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress
Authors: Li, Liang
Chan, Jeremy Soon Kiat
Tan, Ming Jie
Sng, Ming Keat
Teo, Ziqiang
Phua, Terri
Choo, Chee Chong
Zhu, Pengcheng
Tan, Nguan Soon
Keywords: Cancer-associated Fibroblasts
DRNTU::Science::Biological sciences
Oxidative Stress
Issue Date: 2017
Source: Chan, J. S. K., Tan, M. J., Sng, M. K., Teo, Z., Phua, T., Choo, C. C., . . . Tan, N. S. (2017). Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress. Cell Death & Disease, 8(1), e2562-. doi:10.1038/cddis.2016.492
Series/Report no.: Cell Death & Disease
Abstract: Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H2O2 secretion compared with normal fibroblasts (FIBs). These results suggest that extracellular H2O2 acts as a field effect carcinogen. Indeed, H2O2-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H2O2 resulted in the acquisition of an oxidative, CAF-like state. In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H2O2 production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways.
DOI: 10.1038/cddis.2016.492
Rights: © 2017 The Author(s) (Nature Publishing Group). Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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