TY - JOUR
T1 - Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells
AU - Guillem-Llobat, Paloma
AU - Dovizio, Melania
AU - Bruno, Annalisa
AU - Ricciotti, Emanuela
AU - Cufino, Valerio
AU - Sacco, Angela
AU - Grande, Rosalia
AU - Alberti, Sara
AU - Arena, Vincenzo
AU - Cirillo, Mariangela
AU - Patrono, Carlo
AU - Fitzgerald, Garret A.
AU - Steinhilber, Dieter
AU - Sgambato, Alessandro
AU - Patrignani, Paola
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Aspirin
KW - Colorectal cancer
KW - Epithelial-mesenchymal transition
KW - Metastasis
KW - Oncology
KW - Platelets
KW - Aspirin
KW - Colorectal cancer
KW - Epithelial-mesenchymal transition
KW - Metastasis
KW - Oncology
KW - Platelets
UR - http://hdl.handle.net/10807/95017
UR - http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=download&path%5b%5d=8655&path%5b%5d=25920
U2 - 10.18632/oncotarget.8655
DO - 10.18632/oncotarget.8655
M3 - Article
SN - 1949-2553
VL - 7
SP - 32462
EP - 32477
JO - Oncotarget
JF - Oncotarget
ER -