In order to grow beyond minimal size (3 mm3), tumors must generate a new vascular supply (angiogenesis) for the purpose of gas exchange, cell nutrition, and waste disposal. Among many angiogenic factors, VEGF-A has been shown to be the most important one in tumor angiogenesis and associated microvessel permeability to plasma proteins. A humanized antibody to VEGF-A165, Avastin, has been developed and shown to be effective in treating several types of cancers. However, Avastin has significant toxic side effects. Therefore, it is desirable to identify whether downstream targets of VEGF signaling can be used as promising therapeutic targets with less toxic effects. Our recent work showed that the orphan nuclear receptor TR3 (mouse analogue, Nur77) was highly upregulated by VEGF-A165 in cultured endothelial cells and in pathological angiogenesis and that it was required for VEGF-A165-induced endothelial cell proliferation and survival in vitro and Matrigel angiogenesis in vivo. Overexpression of TR3 cDNA induced endothelial cell proliferation and survival in vitro and in Matrigel angiogenesis in vivo, even in the absence of VEGF-A165. The transcriptional activity of TR3 is required for its function in angiogenesis. Further, B16 melanoma growth was completely inhibited in Nur77-/- mice, most likely through inhibition of tumor angiogenesis. Nur77-/- mice have no obvious developmental defect. Our overall hypothesis is that TR3/Nur77 regulates tumor growth through regulation of angiogenesis and associated microvessel permeability. To prove our hypothesis and gain insight into the molecular mechanisms, we will study tumor growth in transgenic mice that Nur77 activity is inhibited in mouse endothelium in Aim 1.
Our second aim will investigate that TR3/Nur77 regulates tumor angiogenesis and its associated microvessel permeability by destabilization of VE-cadherin adherences junctions. In the last aim, we will delineate the transcriptional mechanisms by which TR3 regulates VE-cadherin expression. The information from this study will not only enhance our understanding of the pathophyiosiology of tumorigenesis but also help us to develop effective therapeutic approaches for treatment of cancers.
