Role of TRAF6 as a Regulator of Endothelial Cell Activation and Angiogenesis (88.20)

Tumor angiogenesis and metastasis are dependent on tumor-secreted growth factors and pro-inflammatory signals that target receptors on endothelial cells. The signaling cascade that emanates from many of these receptors is mediated by the adaptor molecule and signal transducer TRAF6. To date, however, the intrinsic effect of TRAF6 in endothelial cell biology has not been examined in detail. Most importantly, its effect on angiogenesis, tumor growth and metastasis has not been investigated in vivo. We hypothesize that, by acting as a molecular convergence point in the signaling downstream of different pro-inflammatory and pro-angiogenic stimuli, TRAF6 is a chief regulator of endothelial cell activation and angiogenesis to drive tumor growth and metastasis. To test this hypothesis, we have generated transgenic mice that lack TRAF6 specifically in endothelial cells (TRAF6-ΔE) to use as a novel in vivo model of angiogenesis and metastasis. Using in vitro angiogenic tests, we have found that TRAF6-deficient endothelial cells have impaired angiogenic properties, and using two different tumor models we have demonstrated that endothelial cell-expressed TRAF6 has an essential role in tumor growth.