Exosomal HMGB1 Promoted Cancer Malignancy

SIMPLE SUMMARY: In addition to their role in hemostasis and thrombosis, platelets have been implicated in cancer malignancy and thrombocytosis in cancer patients and have been associated with an adverse prognosis. These phenomena indicate that antiplatelet drugs may be useful as an anticancer therapy. Using K562-differentiated megakaryocytes and murine platelets, conditioned medium and exosomes obtained from megakaryocytes and platelets contained high-mobility group box 1 (HMGB1) and promoted cancer cell survival, as well as protected cancer cells from doxorubicin cytotoxicity. Data of tumor-bearing mice established by Lewis lung carcinoma (LLC) cells and C57BL/6 mice revealed that antiplatelet drug dipyridamole and exosome release inhibitor GW4869 mitigated tumor growth and ameliorated concurrent alterations in blood circulation and tumor tissues, as well as platelet infiltration in tumor tissues. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment. ABSTRACT: 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-β1), 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.