Cancer-associated Fibroblasts Promote Irradiated Cancer Cell Recovery Through Autophagy

EBioMedicine

Jiangmin Zhao¹  Bocheng Wang¹  Jinliang Wu¹  Dan Zhu¹  Hongxiu Han¹  Yongbin Wang²  Jun Mi²  Guifang Gan²  Yuan Cao²  Xiaona Wang²  Yan Xu²  Xiaoling Li³  Ming Ye⁴ 

[1] 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China;Department of Biochemistry & Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China;NIEHS, National Institute of Health, United States;Renji Hospital, Shanghai Jiao Tong University School of Medicine, China;

关键词: Cancer-associated fibroblast;    Cytokines;    Intermediate metabolite;    Autophagy;    Tumor relapse;    Radiation therapy;   

DOI  :  10.1016/j.ebiom.2017.02.019

来源: DOAJ

【 摘 要 】

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 β-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.

【 授权许可】

Unknown