OncoTargets and Therapy (Feb 2024)
Exosome-Delivered EGFR Induced by Acidic Bile Salts Regulates Macrophage M2 Polarization to Promote Esophageal Adenocarcinoma Cell Proliferation
Abstract
Chuangui Chen,1,2,* Jinsheng Ding,3,* Zhao Ma,1 Yongjie Xie,3 Linhua Zhang,4 Dunwan Zhu4 1Department of Minimally Invasive Esophagus Surgery, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China; 2Beijing Viewsolid Biotechnology Co., LTD, Beijing, 102200, People’s Republic of China; 3Department of Pancreatic Cancer, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People’s Republic of China; 4Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dunwan Zhu, Tianjin Key Laboratory of Biomedical Materials, Key Laboratory of Biomaterials and Nanotechnology for Cancer Immunotherapy, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, 236 Baidi Road, Nankai District, Tianjin, 300192, People’s Republic of China, Tel +86-13034380016, Fax +86-2223340123, Email [email protected]: Chronic gastroesophageal reflux disease (GERD) causes the abnormal reflux of acid and bile salts, which would induce Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). EGFR, as one of main components of the exosome, plays an important role in cancer progression. Here, we investigated the role of acidic bile salts (ABS)-induced exosomal EGFR in EAC cell proliferation.Methods: Electronic microscopic examination and Western blot were used to identify exosomes. Western blot, siRNA transfection, enzyme-linked immunosorbent assay, qRT-PCR, cell viability detection, mouse xenograft tumor models, and immunohistochemical staining were performed to study the function of ABS-induced exosomal EGFR in cell proliferation.Results: We found that ABS improved the exosomal EGFR level of normal human esophageal epithelial cells, BE cells, and BE-associated adenocarcinoma cells. The results were confirmed in the serum-derived exosomes from healthy persons and patients suffering from GERD, BE with or without GERD, and EAC with or without GERD. Moreover, cell line-derived exosomal EGFR was found to promote macrophage M2 polarization through the PI3K-AKT pathway. The co-incubation medium of macrophages and exosomes improved cell proliferation and tumor growth, which depended on the exosomal EGFR level. CCL18 was identified as the most effective component of the co-incubation medium to promote EAC cell proliferation by binding to its receptor PITPNM3 in vitro and in vivo.Conclusion: Our findings demonstrate that ABS-induced exosomal EGFR regulates macrophage M2 polarization to promote EAC proliferation. This study provides an important insight into the role of ABS in EAC development.Keywords: cancer progression, pro-oncogenic, PI3K/AKT pathway, CCL18, PITPNM3
