Arsenic May Act as a Pro-Metastatic Carcinogen Through Promoting Tumor Cell-Induced Platelet Aggregation

Keunyoung Kim, Yoon Kyung Heo, Soyoung Chun, Chang Hwan Kim, Yiying Bian, Ok Nam Bae, Moo Yeol Lee, Kyung Min Lim, Jin Ho Chung

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Arsenic-associated carcinogenesis and related mortality are a major public health concern worldwide; however, the underlying mechanism of action remains unclear. Here, we demonstrated that arsenic promotes tumor metastasis by stimulating tumor cell-platelet aggregation (TCPA), which can ultimately increase cancer-related mortality. In freshly isolated human platelets in vitro, arsenic potentiated TCPA prompted by diverse cancer cell lines, which was attributable to increased platelet reactivity to TCPA with respect to thrombin generation and P-selectin, GPIIb/IIIa expression. Consistently, the co-existence of platelets and arsenic significantly enhanced tumor cell adhesion, extravasation and invasion along with increased metastasis-related markers like metallo-matrix proteinase-2 and -9 in vitro, which was attenuated by platelet activation blockers. Importantly, the exposure to arsenic-contaminated drinking water (2 ppm, 3 weeks) in mice in vivo significantly increased the metastasis of intravenously injected melanoma cells into lung. Furthermore, the exposure to arsenic-contaminated drinking water significantly reduced the survival of melanoma cell-injected mice, which was attenuated by the pretreatment of platelet-activation blockers; aspirin and eptifibatide. All these results provide an important clue to understand the mechanism underlying arsenic-associated cancer mortality and its prevention.

Original languageEnglish
Pages (from-to)18-27
Number of pages10
JournalToxicological Sciences
Volume168
Issue number1
DOIs
StatePublished - 1 Mar 2019

Keywords

  • arsenic
  • carcinogenesis
  • platelet
  • tumor cell-platelet aggregation
  • tumor metastasis

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