The tumour suppressor VHL is known to stabilize the ubiquitin ligase Jade-1. Jade-1 targets both phosphorylated and unphosphorylated -catenin, thereby linking VHL function directly to inhibition of Wnt signalling. The von Hippel–Lindau protein pVHL suppresses renal tumorigenesis in part by promoting the degradation of hypoxia-inducible HIF-α transcription factors1; additional mechanisms have been proposed2. pVHL also stabilizes the plant homeodomain protein Jade-1, which is a candidate renal tumour suppressor that may correlate with renal cancer risk3,4,5. Here we show that Jade-1 binds the oncoprotein β-catenin in Wnt-responsive fashion. Moreover, Jade-1 destabilizes wild-type β-catenin but not a cancer-causing form of β-catenin. Whereas the well-established β-catenin E3 ubiquitin ligase component β-TrCP ubiquitylates only phosphorylated β-catenin6, Jade-1 ubiquitylates both phosphorylated and non-phosphorylated β-catenin and therefore regulates canonical Wnt signalling in both Wnt-off and Wnt-on phases. Thus, the different characteristics of β-TrCP and Jade-1 may ensure optimal Wnt pathway regulation. Furthermore, pVHL downregulates β-catenin in a Jade-1-dependent manner and inhibits Wnt signalling, supporting a role for Jade-1 and Wnt signalling in renal tumorigenesis. The pVHL tumour suppressor and the Wnt tumorigenesis pathway are therefore directly linked through Jade-1.

Endothelial cells can serve as plastic paracrine regulators of cancer biology, modulating tumor growth and metastasis.

Background—: Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. Methods and Results—: As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. Conclusions—: The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that interventions that reduce vSMC TF may help to prevent ST and that uremic solutes should be considered as novel risk factors for ST in patients with chronic renal failure.

Although the influence of context‐dependent endothelial cell (EC) regulation of vascular disease and repair is well‐established, the privileged roles ECs play as paracrine regulators of tumor progression has only recently become appreciated. We hypothesized that if the same endothelial physiology governs vascular and cancer biology then EC control in cancer should follow endothelial regulation of vascular health. Healthy ECs promote vascular repair and inhibit tumor invasiveness and metastasis. Dysfunctional ECs have the opposite effects in vascular disease, and we now ask if dysfunctionally activated ECs will promote cancer cell inflammatory signaling and aggressive properties. Indeed, while factors released from quiescent ECs induce balanced inflammatory signaling, correlating with decreased proliferation and invasiveness, factors released from dysfunctional ECs robustly activated NF‐κB and STAT3 signaling within cancer cells, correlating with increased in vitro invasiveness and decreased proliferation and survival. Furthermore, matrix‐embedded dysfunctional ECs stimulated intratumoral pro‐inflammatory signaling and spontaneous metastasis, while simultaneously slowing primary tumor growth, when implanted adjacent to Lewis lung carcinoma tumors. These studies may broaden our appreciation of the roles of endothelial function and dysfunction, increase understanding and control of the tumor microenvironment, and facilitate optimization of anti‐angiogenic and vascular‐modifying therapies in cancer and other diseases.