COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis

Tumor growth depends on nutrients and oxygen supplied by the vasculature through angiogenesis. Here, we show that the chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a member of the nuclear receptor family, is a major angiogenesis regulator within the tumor microenvironment. Conditional ablation of COUP-TFII in adults severely compromised neoangiogenesis and suppressed tumor growth in xenograft mouse models. In addition, tumor growth and tumor metastasis were also impaired in a spontaneous mammary-gland tumor model in the absence of COUP-TFII. We showed that COUP-TFII directly regulates the transcription of Angiopoietin-1 in pericytes to enhance neoangiogenesis. Importantly, provision of Angiopoietin-1 partially restores the angiogenic defects exhibited by the COUP-TFII-deficient mice, which supports the notion that COUP-TFII controls Angiopoietin-1/Tie2 signaling to regulate tumor angiogenesis. Because COUP-TFII has little impact on normal adult physiological function, our results raise an interesting possibility that inhibition of COUP-TFII may offer a therapeutic approach for anticancer intervention.