title: Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells.
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 PGE2in 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.
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Paloma
authors.initials: P
authors.lastname: Guillem-Llobat
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Bruno
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.affiliation: Institute of General Pathology, Catholic University School of Medicine, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Cufino
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Grande
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Alberti
authors.affiliation: Institute of Pathologic Anatomy, Catholic University, School of Medicine, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.affiliation: Institute of Pathologic Anatomy, Catholic University, School of Medicine, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cirillo
authors.affiliation: Institute of Pharmacology, Catholic University, School of Medicine, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Patrono
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.affiliation: Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.affiliation: Institute of General Pathology, Catholic University School of Medicine, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sgambato
authors.affiliation: Department of Neuroscience, Imaging and Clinical Science, Section of Cardiovascular and Pharmacological Sciences, and CeSI-MeT, "G. d'Annunzio" University, School of Medicine, Chieti, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D019073:HT29 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015232:Dinoprostone; D001241:Aspirin
keywords: aspirin; colorectal cancer; epithelial-mesenchymal transition; metastasis; platelets