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Figure 3. Celecoxib prevents CSC growth and tumor angiogenesis by inhibiting the COX-2/PGE2/VEGF and WNT/LGR5 stemness pathways. COX-2 is required for the production of prostanoids, including PGE2, which is released by tumor cells and stromal cells. PGE2 acts in an autocrine/paracrine manner binding to surface members of the prostanoid receptor family (EP1-4) to increase cancer cell stemness, angiogenesis (via production of VEGF and FGF), invasiveness (via matrix metalloproteinases MMP-2, MMP-9) and thereby promotes tumor metastasis. Celecoxib is an anticancer drug that is cytotoxic for CSCs, inhibiting COX-2/PGE2 production and stemness, thereby down-regulating the WNT/LGR5 signalling pathway, inhibiting angiogenesis and promoting the anticancer immune response. CSC: cancer stem cell; CTC: circulating tumor cell; VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; COX-2: Cyclooxygenase-2; PGE2: prostaglandin E2; PGH2: prostaglandin H2; TCF-4: T-cell factor-4; TNIK: Traf2- and Nck-interacting kinase; AA: arachidonic acid