Exosomal HMGB1 Promoted Cancer Malignancy

Cancers

Jiaan-Der Wang¹  Ya-Yu Wang²  Chun-Jung Chen³  Su-Lan Liao³  Cheng-Yi Chang⁴  Wen-Ying Chen⁵  Jian-Ri Li⁶  Shih-Yi Lin⁷  Shi-Wei Huang⁸ 

[1] Children’s Medical Center, Taichung Veterans General Hospital, Taichung City 407, Taiwan;Department of Family Medicine, Taichung Veterans General Hospital, Taichung City 407, Taiwan;Department of Medical Research, Taichung Veterans General Hospital, Taichung City 407, Taiwan;Department of Surgery, Feng Yuan Hospital, Taichung City 420, Taiwan;Department of Veterinary Medicine, National Chung Hsing University, Taichung City 402, Taiwan;Division of Urology, Taichung Veterans General Hospital, Taichung City 407, Taiwan;Institute of Clinical Medicine, National Yang Ming University, Taipei City 112, Taiwan;Translational Cell Therapy Center, China Medical University Hospital, Taichung City 404, Taiwan;

关键词: antiplatelet;    exosome;    HMGB1;    malignancy;   

DOI  :  10.3390/cancers13040877

来源: DOAJ

【 摘 要 】

Reciprocal crosstalk between platelets and malignancies underscores the potential of antiplatelet therapy in cancer treatment. In this study, we found that human chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (HMGB1) is a type of exosomal cargo, and the antiplatelet drugs aspirin and dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous HMGB1, promoted cancer cell survival and protected cells from doxorubicin cytotoxicity. In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-b1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.

【 授权许可】

Unknown