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ALHulais et al. J Cancer Metastasis Treat 2019;5:3 I http://dx.doi.org/10.20517/2394-4722.2018.71 Page 13 of 23

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

derived from the COX-2 production of prostaglandins as cytokine-like factors stimulating growth, CSCs
and metastases [170,171] . Levels of PGE2 correlate with colonic CSC markers (CD133, CD44, LGR5, and SOX2
messenger RNAs) in human colorectal carcinoma samples suggesting that it is a marker for CR-CSC [171] .
Thus, PGE2 induced CSC expansion by activating nuclear factor-kappa B (NF-κB) via the PGE2 receptor 4
(EP4) and PI3K/MAPK signaling, promoting the formation of liver metastases by colorectal cancer cell lines
injected into mice [171] .

Angiogenesis is one of the classical hallmarks of cancer, promoting new blood vessel formation from pre-
existing vessels, thereby facilitating the supply of blood borne nutrients and oxygen to the tumor cells [172] .
As early as 1999, celecoxib was recognized as an important chemotherapeutic agent in colorectal cancer
treatment [173] because of its ability to potently inhibit angiogenesis by preventing vascular endothelial
growth factor (VEGF) and FGF production, reducing growth of gastrointestinal cancer xenografts in nude
mice [174] . COX-2/PGE2 activation increases VEGF expression by colon cancer cells, thereby promoting tumor
angiogenesis (reviewed in [175,176] ).

Evidence for COX-2/PGE playing a role in many other cancer types besides CRC and is a CSC
drug target
These early findings have since been confirmed in many subsequent studies of other cancers as well including
lowering microvessel density in gastric cancer models by inhibiting COX-2 mediated PGE2 production
and VEGF expression [177,178] , and in head and neck [179] , pancreatic [180] , Lewis lung cancers and sarcomas [181]
(reviewed in [182] ). In more recent studies of dimethylhydrazine-induced colorectal cancer models, NSAIDs