P2RY12-Inhibitors Reduce Cancer-Associated Thrombosis and Tumor Growth in Pancreatic Cancers

Abstract

Platelet function can be modified by cancer cells to support tumor growth, causing alterations in the delicate hemostatic equilibrium. Cancer-cell and platelet interactions are one of the main pillars of Trousseau’s syndrome: a paraneoplastic syndrome with recurring and migrating episodes of thrombophlebitis. Altogether, this leads to a four-fold risk of thrombotic events in cancer patients, which in turn, portend a poor prognosis. We previously demonstrated that anti-P2RY12 drugs inhibit cancer-associated-thrombosis and formation of tumor metastasis in pancreatic cancer models. Here, we aimed to (1) compare the effects of aspirin and clopidogrel on pancreatic cancer prevention, (2) characterize the effects of clopidogrel (platelet P2RY12 inhibitor) on cancer-associated thrombosis and cancer growth in vivo, (3) determine the effect of P2RY12 across different digestive-tract cancers in vitro, and (4) analyze the expression pattern of P2RY12 in two different cancer types affecting the digestive system. Clopidogrel treatment resulted in better survival rates with smaller primary tumors and less metastasis than aspirin treatment. Clopidogrel was also more effective than aspirin at dissolving spontaneous endogenous thrombi in our orthotopic advanced cancer mouse model. P2RY12 expression gives pancreatic adenocarcinomas proliferative advantages. In conclusion, we propose the hypothesis that clopidogrel should be further studied to target and prevent Trousseau’s syndrome; as well as diminish cancer growth and spread. However, more studies are required to determine the implicated pathways and effects of these drugs on cancer development.

Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

“…The pancreatic cancer microenvironment is highly rich in tumor-associated neutrophils, platelets and NETs ( 416 ). Clopidogrel was shown to inhibit cancer growth and metastasis in PANC02 pancreatic cancer model ( 417 ). In the future, it will be important to analyse the effect of P2Y12 blockers on cancer-associated neutrophil activation and NETosis.…”

Neutrophils, Cancer and Thrombosis: The New Bermuda Triangle in Cancer Research

“…More traditionally used anticoagulant and anti-platelet drugs like low molecular weight or unfractioned heparin or direct-acting oral anticoagulants (Apixaban, dabigatran, rivaroxaban or endoxaban) continue to be the gold standard for thrombosis treatment in CAT [115,116]. Recently, the use of platelet P2RY12 inhibitors has been proposed to both prevent and treat TCIPA and CAT, but this application has not yet been validated in clinical trials [15,117].…”

“…In a direct manner, platelet receptors like αIIbβ3 and αVIβ1 can bind to tumor αVβ3 and ADAM9 respectively, as well as binding with P-selectins through PSGL-1 interaction, platelet toll-like receptor 4 and facilitating CLEC2-podoplanin interactions [10][11][12][13][14]. In an indirect manner, tumor cells secrete platelet agonists (like thromboxane A2 and ADP) into the tumor microenvironment, activating platelets which then release more platelet agonists and create a potent activation loop [11][12][13]15]. Tumor-activated platelets can also secrete growth factors into the tumor microenvironment like transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) [2,13,16].…”

Platelets involved tumor cell EMT during circulation: communications and interventions

“…Both activated platelets and tumor cells release ADP, which promotes tumor-induced platelet aggregation. ADP binding receptor P2Y12 inhibitors, such as clopidogrel and ticagrelor, hinder platelet activation and reduce TCIPA by preventing ADP from binding platelets [ 110 , 111 ]. Preclinical researches have shown that P2Y12 inhibitors can reduce metastasis in melanoma, ovarian, breast, lung, and pancreatic cancers [ 56 , 112 – 115 ].…”

“…Preclinical researches have shown that P2Y12 inhibitors can reduce metastasis in melanoma, ovarian, breast, lung, and pancreatic cancers [ 56 , 112 – 115 ]. In pancreatic cancer cells, P2Y12 has been found to be specifically expressed and confer a proliferative advantage on tumor cells, and clopidogrel treatment can inhibit the formation of cancer-associated-thrombosis and tumor metastasis [ 110 ], suggesting that the blocking of P2Y12 has a dual antitumor effect on pancreatic cancer cells.…”