Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells

Vincenzo Arena, Alessandro Sgambato, Carlo Patrono, Paloma Guillem-Llobat, Melania Dovizio, Annalisa Bruno, Emanuela Ricciotti, Angela Sacco, Rosalia Grande, Sara Alberti, Garret A. Fitzgerald, Dieter Steinhilber, Paola Patrignani

Risultato della ricerca: Contributo in rivistaArticolo in rivista

94 Citazioni (Scopus)

Abstract

We investigated whether platelets prime colon cancer cells for metastasis and whether pharmacological inhibition of platelet function may prevent it. Coculturing HT29 human colon carcinoma cells with human platelets led to the induction of mesenchymal-like cancer cells characterized by downregulation of E-cadherin and upregulation of Twist1, enhanced cell mobility and a proaggregatory action on platelets. These changes were prevented by different antiplatelet agents, aspirin[an inhibitor of cyclooxygenase(COX)-1], DG-041[an antagonist of prostaglandin(PG)E2 EP3 receptor] and ticagrelor (a P2Y12 receptor antagonist). The injection of HT29 cells, exposed to platelets in vitro, into the tail vein of humanized immunodeficient mice led to higher incidence of lung metastasis compared to the injection of untreated HT29 cells. This effect was associated with enhanced systemic biosynthesis of thromboxane(TX)A2 and PGE2 in vivo. Platelet COX-1 inhibition by aspirin administration to mice prevented the increased rate of metastasis as well as the enhanced production of TXA2 and PGE2 induced by the in vitro priming of HT29 cells by platelets. In conclusion, targeting platelet COX-1 with low-dose aspirin exerts an antimetastatic action by averting the stem cell mimicry of cancer cells associated with enhanced proaggregatory effects induced by platelet-tumor cell interactions. These effects may be shared by other antiplatelet drugs.
Lingua originaleEnglish
pagine (da-a)32462-32477
Numero di pagine16
RivistaOncotarget
Volume7
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Aspirin
  • Colorectal cancer
  • Epithelial-mesenchymal transition
  • Metastasis
  • Oncology
  • Platelets

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