Exosomal HMGB1 Promoted Cancer Malignancy.

Jiaan-Der Wang,Su-Lan Liao,Cheng-Yi Chang,Shi-Wei Huang,Ya-Yu Wang,Shih-Yi Lin,Chun-Jung Chen,Wen-Ying Chen,Jian-Ri Li

doi:10.3390/cancers13040877

Abstract

Simple SummaryIn 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.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.

Highlights

Bloodstream platelets are small anucleated cell fragments released from bone marrow megakaryocytes
Conditioned medium of K562/phorbol 12-myristate 13-acetate (PMA)-differentiated megakaryocytes promoted T24 cell survival, and the effects were attenuated by the presence of dipyridamole, aspirin, or cytochalasin D during megakaryocytic differentiation (Figure 1E)
The findings suggest the potential release of pro-survival molecules by K562/PMA-differentiated megakaryocytes, and the recipient cells likely have an intact actin cytoskeleton to respond to

Summary

Introduction

Bloodstream platelets are small anucleated cell fragments released from bone marrow megakaryocytes. Besides their key roles in hemostasis and thrombosis, multifunctional platelets are involved in numerous biological activities, including malignancy. Thrombocytosis is an adverse prognostic factor of malignancies. Cancer patients often exhibit thrombocytosis and platelet activation, which improve after surgical removal of the tumor mass [1,2,3]. Clinical and experimental findings indicate that defective platelet release, reduction of platelet count, and inactivation of platelets relieve tumor burden [4,5,6]. Despite advances in tumor treatments, therapeutic outcomes of malignancies are still unsatisfactory. A comprehensive understanding of the crosstalk between platelets and malignancies may facilitate the development of molecular-based alternative strategies for combating malignancy

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