Oncotarget

Research Papers:

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

Paloma Guillem-Llobat _, Melania Dovizio, Annalisa Bruno, Emanuela Ricciotti, Valerio Cufino, Angela Sacco, Rosalia Grande, Sara Alberti, Vincenzo Arena, Mariangela Cirillo, Carlo Patrono, Garret A. FitzGerald, Dieter Steinhilber, Alessandro Sgambato and Paola Patrignani

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Oncotarget. 2016; 7:32462-32477. https://doi.org/10.18632/oncotarget.8655

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Abstract

Paloma Guillem-Llobat1,*, Melania Dovizio1,*, Annalisa Bruno1,*, Emanuela Ricciotti2, Valerio Cufino3, Angela Sacco1, Rosalia Grande1, Sara Alberti1, Vincenzo Arena4, Mariangela Cirillo4, Carlo Patrono5, Garret A. FitzGerald2, Dieter Steinhilber6, Alessandro Sgambato3, Paola Patrignani1

1Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, “G. d’Annunzio” University, School of Medicine, Chieti, Italy

2Institute for Translational Medicine and Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA

3Institute of General Pathology, Catholic University School of Medicine, Rome, Italy

4Institute of Pathologic Anatomy, Catholic University, School of Medicine, Rome, Italy

5Institute of Pharmacology, Catholic University, School of Medicine, Rome, Italy

6Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany

*These authors have contributed equally to this work

Correspondence to:

Paola Patrignani, email: ppatrignani@unich.it

Keywords: aspirin, colorectal cancer, metastasis, platelets, epithelial-mesenchymal transition

Received: January 28, 2016    Accepted: March 28, 2016    Published: April 08, 2016

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.


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