Journal
EBIOMEDICINE
Volume 17, Issue -, Pages 45-56Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.02.019
Keywords
Cancer-associated fibroblast; Cytokines; Intermediate metabolite; Autophagy; Tumor relapse; Radiation therapy
Funding
- National Program on Key Basic Research Project (973 Program) [2012CB910102]
- Shanghai Municipal Science and Technology Commission [11DZ2260200]
- National Science Foundation of China [81372194, 81572300]
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Tumor relapse after radiotherapy is a significant challenge to oncologists, even after recent the advances in technologies. Here, we showed that cancer-associated fibroblasts (CAFs), a major component of cancer stromal cells, promoted irradiated cancer cell recovery and tumor relapse after radiotherapy. We provided evidence that CAFs-produced IGF1/2, CXCL12 and beta-hydroxybutyrate were capable of inducing autophagy in cancer cells post-radiation and promoting cancer cell recovery from radiation-induced damage in vitro and in vivo in mice. These CAF-derived molecules increased the level of reactive oxygen species (ROS) post-radiation, which enhanced PP2A activity, repressing mTOR activation and increasing autophagy in cancer cells. Consistently, the IGF2 neutralizing antibody and the autophagy inhibitor 3-MA reduce the CAF-promoted tumor relapse in mice after radiotherapy. Taken together, our findings demonstrated that CAFs promoted irradiated cancer cell recovery and tumor regrowth post-radiation, suggesting that targeting the autophagy pathway in tumor cells may be a promising therapeutic strategy for radiotherapy sensitization. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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