Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression
Year: 2019
Type: article
Abstract: Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence-associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD-L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME-mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging-related morbidity and mortality.
Source: Aging Cell
DOI: 10.1111/acel.13027
Institutions: Shanghai Jiao Tong University, Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, Shanghai Medical College of Fudan University, Fudan University, Zhongshan Hospital, Tongji University, Shanghai Tenth People's Hospital, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, China Medical University, Soochow University, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Imperial College London, Buck Institute for Research on Aging, Lawrence Berkeley National Laboratory, University of Washington
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,900
Funders: U.S. Department of Defense, Cancer Research UK, National Institute for Health and Care Research, National Natural Science Foundation of China, Chinese Academy of Sciences, Breast Cancer Now, National Institutes of Health, Imperial Experimental Cancer Medicine Centre, Medical Research Council, National Key Research and Development Program of China, NIHR Imperial Biomedical Research Centre, National Center for Advancing Translational Sciences, DOD Prostate Cancer Research Program
Awards: 锌指蛋白Zscan4在衰老相关分泌表型发生发展中的作用与机制研究, G1423095550, G1731248541, G2352332186, G2362268443, G3295720644, G397041384, G422437481, G5033475478, G5099032530, University of Pittsburgh Clinical and Translational Science Institute, Targeting the FOXM1 signature for early diagnosis and treatment in cholangiocarcinoma, G7311530153, G7318569333, G7642598643, G7707903813, G8595049424, G885334847, G9000042296, G9000150061, G924014597
OpenAlex ID: W2972176863