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.
Highlights
The acquisition of a mesenchymal-like phenotype by colorectal cancer cells has been recognized as a relevant phenomenon in the development of metastasis by promoting cancer cell intravasation and extravasation [1]
We developed an experimental mouse model of hematogenous metastases, where immunodeficient NOD-scid IL2Rγnull (NSG) mice were injected via the tail vein with HT29 cells and the formation of lung metastases was quantified after 7 days
We have shown that HT29 cells exposed in vitro to platelets acquire a mesenchymal-like invasive phenotype associated with enhanced capacity to activate platelets in vivo and that the exposure of HT29 cells to aspirinated platelets prevented the induction of epithelial-to-mesenchymal transition (EMT) and migration in cancer cells
Summary
The acquisition of a mesenchymal-like phenotype by colorectal cancer cells has been recognized as a relevant phenomenon in the development of metastasis by promoting cancer cell intravasation and extravasation [1]. Post-hoc analyses of randomized controlled trials with daily aspirin, designed to evaluate its efficacy in cardiovascular prevention, have shown that aspirin, at doses as low as 75-100 mg/day, reduces the incidence of cancer deaths possibly as a consequence of the prevention of distant metastases [7,8] This chemopreventive effect was seen in the Thrombosis Prevention Trial (TPT) [9] with a controlled-release matrix formulation of aspirin 75 mg daily which restricts the inhibitory effect of aspirin on platelet cyclooxygenase (COX)-1 to the presystemic compartment, preserving the increase in vascular prostacyclin (PGI2) evoked by systemic administration of bradykinin, as reflected by the urinary levels of 2,3-dinor6-keto-PGF1α(PGI-M), a major metabolite of vascular PGI2 [10]. The mechanism of action of aspirin in the prevention of cancer metastases is still under debate
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