Abstract
Platelets, beyond their role in hemostasis and thrombosis, may sustain tumorigenesis and metastasis. These effects may occur via direct interaction of platelets with cancer and stromal cells and by the release of several platelet products. Platelets and tumor cells release several bioactive molecules among which a great amount of adenosine triphosphate (ATP) and adenosine diphosphate (ADP). ADP is also formed extracellularly from ATP breakdown by the ecto-nucleoside-triphosphate-diphosphohydrolases. Under ATP and ADP stimulation the purinergic P2Y1 receptor (R) initiates platelet activation followed by the ADP-P2Y12R-mediated amplification. P2Y12R stimulation amplifies also platelet response to several platelet agonists and to flow conditions, acting as a key positive feed-forward signal in intensifying platelet responses. P2Y12R represents a potential target for an anticancer therapy due to its involvement in platelet-cancer cell crosstalk. Thus, P2Y12R antagonists, including clopidogrel, ticagrelor, and prasugrel, might represent potential anti-cancer agents, in addition to their role as effective antithrombotic drugs. However, further studies, in experimental animals and patients, are required before the recommendation of the use of P2Y12R antagonists in cancer prevention and progression can be made.
Highlights
The number of cancer cases, which are diagnosed each year continues to rise, primarily due to an aging population
Several lines of evidence show that the cross-talk of cancer cells with stromal cells and platelet-derived products induce a novel phenotype, which allows them to invade the healthy tissue around, to enter the bloodstream and to colonize distant tissues
Platelets and cancer cells have been shown to release a significant amount of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) (Beigi et al, 1999; Pellegatti et al, 2008; Burnstock and Di Virgilio, 2013)
Summary
The number of cancer cases, which are diagnosed each year continues to rise, primarily due to an aging population. In a rat model of tongue cancer pain, obtained by inoculation of squamous cell carcinoma cells, a marked activation of microglia through P2Y12R was found in the trigeminal spinal subnucleus caudalis This resulted to be associated with increased excitability of nociceptive neurons and consequent allodynia after mechanical stimulation. In a mouse model of either spontaneous or experimentally induced lung metastasis, obtained by injection of Lewis lung carcinoma (LLC) cells and B16 melanoma cells respectively, P2Y12 deficiency reduced the weight of lung metastasis without affecting the primary tumors (Wang et al, 2013) This suggests a role for the ADP receptor in promoting the metastatic process. These data do not support concerns for a class effect of thienopyridines in increasing the cancer event rate and/or mortality (Kotronias et al, 2017)
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