Journal
AGING CELL
Volume 18, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/acel.13027
Keywords
aging; amphiregulin; cancer resistance; clinical biomarker; combinational treatment; programmed cell death 1 ligand; senescence-associated secretory phenotype; stroma
Categories
Funding
- National Key Research and Development Program of China [2016YFC1302400]
- National Natural Science Foundation of China [81472709, 31671425, 31871380]
- National Natural Science Foundation of China (NSFC) [81472709, 31671425, 31871380, 81472228, 81201535, 81302065, 81472202]
- Key Lab of Stem Cell Biology of Chinese Academy of Sciences
- U.S. Department of Defense (DoD) Prostate Cancer Research Program (PCRP) [PC111703]
- Clinical Science and Technology Innovation Project of Shanghai [SHDC12016104]
- NIH [TR000005]
- Give Breast Cancer The Boot Program
- Friends for an Earlier Breast Cancer Test Program
- CRUK [A12011]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- Medical Research Council of the United Kingdom [MR/N012097/1]
- Cancer Research UK Imperial Centre, Imperial ECMC
- NIHR Imperial BRC
- MRC [MR/N012097/1] Funding Source: UKRI
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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.
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