The expression and activity of COX-1 in HUVEC regulates the formation of tubular structures induced by cancer cells (Tsujii et al., 1998). LL-37, the only cathelicidin protein expressed by humans, upregulated in breast, ovarian and lung tumors (Larrick et al., 1995; Coffelt et al., 2009; Weber et al., 2009; Haussen et al., 2008).The Cathelicidin LL-37 can induce a proangiogenic response via cPLA2-COX-1-PGE2-EP3 Signaling in human ECs, which is suppressed by aspirin in a manner of inhibiting COX-1 in vivo (Salvado et al., 2013) (Figure 2). Activation of PGE2/EP3 axis promotes sprouting angiogenesis by suppression of protein kinase A (PKA)/p-S675- β-catenin/Notch signaling in ECs (Chen et al., 2017). Moreover, fibroblast growth factor-1 and fibroblast growth factor-2 are the first two discovered polypeptides showing proangiogenic effects (Thomas et al., 1985; Esch et al., 1985). FGFR1 (Fibroblast Growth Factor Receptor 1) pathway in microvascular endothelial cells can be activated by EP3 receptor signal mediation (Federica et al., 2008). The 2,5-dihydroxyphenylic acids (Gentisic Acid), a metabolite of Aspirin, is a powerful fibroblast growth factor Inhibitor (Grootveld et al., 1998; Fernández et al., 2010). Furthmore, angiogenic effects of PGE2 are mediated by up-regulation of the C-X-C chemokine receptor type 4 (CXCR4) and CXCR4 expression can be inhibited by aspirin in HMECs (Rosalba et al., 2003). However, it warrants further research to verify the downstream of cPLA2-COX-1-PGE2-EP3 signalling transduction when aspirin antiangiogenesis.
Figure 2 Shown some signalling pathways that are targets of aspirin to inhibit tumor angiogenesis.However, it warrants further study to verify the downstream of signalling transduction in these pathways.
It has been demonstrated that COX-2 in ECs is vital in regulating angiogenesis, and the microvessel density relate to the level of COX-2 expression (Jones et al., 1999; Kazuhiko et al., 2000). Moreover, in the sponge implanted mouse model, COX-2 mediated prostaglandins can up-regulate the expression of VEGF mRNA (Yoshida et al., 2003).
However, aspirin effectively inhibits COX-1 activity at a pharmacological concentration, but has a weaker active to block COX-2 activity (Meade et al., 1993; Mitchell et al., 1993). In fact, it has been demonstrated that salicylate inhibits Cyclooxygenase-2 transcription induced by IL-1β or phorbol 12-myristate 13-acetate by blocking C/Enhancer-binding Protein β binding to its cognate site on Cyclooxygenase-2 promoter (Michael et al., 2001). Furthermore, aspirin and sodium salicylate at pharmacological concertration blocked COX-2 protein expresion induced by cancer and VEGF (Shtivelband et al., 2003) (Figure 2). COX-2 protein levels in HUVECs, inducing by PMA (Porbolol 12-myristate 13-acetate), inhibited by Aspirin and sodium salicylate in the manner of concentration-dependent (Xu et al., 1999). Therefore, aspirin may inhibit COX-1 activity and COX-2 transcription to regulate angiogenesis.