2.1 Effect on Heparanase and the matrix metalloproteinases
Heparanase,the heparan sulfate (HS)-degrading endo-β-D-glucuronidase,could regulate angiogenesis and degrade the HS chain of heparan sulfate proteoglycans in the extracellular matrix (Li et al., 2009; Vlodavsky et al., 2018). After the extracellular matrix collapses, heparin-binding cytokines such as HGF, VEGF, and bFGF are released to promote tumor angiogenesis (Talmadge et al., 2010; Vlodavsky et al., 2001). Notably, except for the members of FGF-19 subfamily with little or no affinity for these glycosaminoglycans,all fibroblast growth factors high affinitive bind to heparin (Asada et al., 2009). Heparanase is inhibited by aspirin which directly bind to Glu150 (human Q9Y251: Glu 225) region and thereby suppress the vascular structures formation in a dose-dependent manner (Dai et al., 2017). Salicylic acid also has the same effect of inhibiting the heparanase activity (Dai et al., 2017). Therefore, aspirin or salicylic acid may reduce release of heparin-binding cytokines such as HGF, VEGF, and bFGF, thereby inhibiting angiogenesis.
The matrix metalloproteinases (MMPs), a large family of zinc-dependent endoproteases, can remodel and degrade the components in the extracellular matrix (ECM) and could play a vital role in angiogenesis (Kapoor et al., 2016). The degradation effect of Gelatinase-B (MMP-9) in the extracellular matrix promotes the migration of ECs to angiogenesis stimuli (Hiraoka et al., 1998; Puyraimond et al., 1999). Moreover, MMP-9 can degrade the Multimerin 2, which is tightly juxtaposed with ECs surface and bind proangiogenic cytokines to exert angiostatic functions (Andreuzzi et al., 2017; Christian et al., 2001). Metalloproteinase 1 (TIMP-1) as a specific tissue inhibitor could inhibit MMP-9 and suppress the ECM degradation in tumor angiogenesis (Khokha et al., 1994). In addition, it has been demonstrated that MMP-9 can induce the expression of VEGF (Bergers et al., 2000). Interesting, aspirin can suppress the levels of secreted MMP-9 activity and increase the levels of secreted TIMP-1 activity in the cancer cell (Shi et al., 2017). In this way, aspirin may inhibit migration of ECs to angiogenesis stimuli in the tumor microenvironment. Furthermore, EP3 receptor signal transduction on ECs is crucial for MMP-9 upregulation, which can enhance tumor angiogenesis (Amano et al., 2008). It has been demonstrated that aspirin can reduce MMP-9 upregulation by inhibiting cPLA2-COX-1-PGE2-EP3 Signaling in ECs (Salvado et al., 2013).
2.2 Effect on Cyclooxygenase of endothelial cells