title: Cancer-associated Fibroblasts Promote Irradiated Cancer Cell Recovery Through Autophagy.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Guifang
authors.initials: G
authors.lastname: Gan
authors.affiliation: 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Bocheng
authors.initials: B
authors.lastname: Wang
authors.affiliation: 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Wang
authors.affiliation: 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Han
authors.affiliation: NIEHS, National Institute of Health, United States.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Renji Hospital, Shanghai Jiao Tong University School of Medicine, China. Electronic address: yeming@renji.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.affiliation: 9th Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, China. Electronic address: johnmzhao@sjtu.edu.cn.
authors.forename: Jiangmin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 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. Electronic address: jmei@sjtu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Mi
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D008175:Lung Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D017382:Reactive Oxygen Species; C025946:3-methyladenine; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2; D000225:Adenine; D020155:3-Hydroxybutyric Acid
keywords: Autophagy; Cancer-associated fibroblast; Cytokines; Intermediate metabolite; Radiation therapy; Tumor relapse