The COX-2–PGE2 pathway drives angiogenesis, tumor growth, and metastasis independent of VEGF.

  • Major finding: The COX-2–PGE2 pathway drives angiogenesis, tumor growth, and metastasis independent of VEGF.

  • Mechanism: PGE2 promotes angiogenesis via direct stimulation of vasculature and indirect myeloid-cell recruitment.

  • Impact: COX-2 inhibition may represent a useful strategy to bypass VEGF resistance and prevent metastasis.

Tumor neovascularization is largely driven by VEGF, which has led to the development of small-molecule inhibitors targeting this pathway, including the selective compound axitinib. Despite the clinical activity of these compounds, tumor angiogenesis persists in the presence of VEGF/VEGF receptor (VEGFR) inhibitors; indicating that alternative angiogenic factors are likely to contribute to tumor vascularization. In an effort to identify VEGF-independent angiogenic mechanisms, Xu and colleagues showed that the tumorigenic potential of VEGFR-inhibitor–refractive murine colon cancer cells failed to correlate with VEGF levels, but rather was linked to expression of prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX-2), a rate-limiting enzyme in PGE2 production. Inhibition of COX-2 via celecoxib treatment reduced tumor growth in vivo without affecting VEGF levels, and forced COX-2 expression in poorly tumorigenic cells enhanced tumor formation and angiogenesis via a VEGF-independent increase in PGE2 production and myeloid-cell recruitment. Further evidence that COX-2–PGE2 signaling drives angiogenesis independent of VEGF was provided by the findings that COX-2 expression rescued angiogenesis and tumor growth in VEGF-deficient colon cancer xenografts and that inhibition of VEGF via axitinib or the VEGF blocking antibody DC1O1 was unable to prevent COX-2–PGE2-induced angiogenesis. Importantly, treatment with celecoxib and DC1O1 or axitinib reduced tumor growth and angiogenesis to a greater extent than that observed with single-agent therapy, suggesting that cotargeting of these pathways leads to a synergistic inhibition of angiogenesis. Furthermore, dual inhibition of the COX-2 and VEGF pathways led to a dramatic reduction in both spontaneous and preexisting tumor metastasis and extended overall survival in several in vivo cancer models. Together, these findings emphasize the role of the COX-2–PGE2 pathway in VEGF-independent angiogenesis and provide a rationale for the clinical use of COX-2 inhibitors in combination with VEGFR blockade in patients with established metastatic disease.

Xu L, Stevens J, Hilton MB, Seaman S, Conrads TP, Veenstra TD, et al. COX-2 inhibition potentiates antiangiogenic cancer therapy and prevents metastasis in preclinical models. Sci Transl Med 2014;6:242ra84.

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