2.3 Effect on platelet-mediated angiogenesis
Platelets are considered to be the main actors in each step of angiogenesis as they store various growth factors, proteases, cytokines, chemokines and cell adhesion molecules (Patzelt et al., 2012; Pipili-Synetos et al., 1998). Therefore, pharmacological interventions of platelet-associated proangiogenic activity have been recognized as a important adjuvant treatment for cancer (Bambace et al., 2011; Radziwon-Balicka et al., 2012).
The 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), a direct COX-1 product in platelet, can combine with other pro-angiogenic factors released by platelets to regulate angiogenesis (Rauzi et al., 2016). Aspirin can block the angiogenic response of thrombin-stimulated human platelets in human microvascular endothelial cells (HMEC-1) (Etulain et al., 2013). In addition, aspirin inhibits 15(S)-HETE production in platelet with inhibition COX-1 to reduce angiogenesis, which also provide a explanation for the protective effects of low-dose aspirin on some cancers (Rauzi et al., 2016) (Figure 2). A study demonstrates that 15(S)-HETE can promote angiogenesis in HuDMECs through the PI3K-Akt-mTOR-S6K1 signaling pathway (Zhang et al., 2005). However, it warrants further study to verify the downstream of 15(S)-HETE signalling transduction when aspirin antiangiogenesis.
Platelet levels of thrombospondin-1 (TSP-1) have been indicated to regulate early stage of tumor angiogenesis (Zaslavsky et al., 2010). In breast cancer patients, taking aspirin therapy can upregulate TSP-1 level without a concurrent increase in VEGF levels in platelets (Holmes et al., 2013). It is also indicated that pretreatment with aspirin could reduce the amount of VEGF released from platelets at rest and after being activated by ADP or interacting with MCF-7 cells (Battinelli et al., 2011). Furthermore, aspirin may correct abnormal platelet activation, prevent the release of a large number of angiogenesis regulators, and then help normalize the tumor vasculature and shape the tumor microenvironment, thereby reducing tumor invasion and progression (Su et al., 2014). There is a registered clinical trial to test the efficacy of aspirin use for exploring the platelet function of its mechanism of action, such as the change levels of COX-1, thrombospondin 1, NF-Kb and VEGF (Table1).