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