Isoforms of endothelin-converting enzyme-1 (ECE-1) have opposing effects on prostate cancer cell invasion

Cross-talk between tumour and stromal cells can profoundly influence cancer cell invasion by increasing the availability of mitogenic peptides such as endothelin-1 (ET-1). Endothelin-1 is elevated in men with metastatic prostate cancer (PC), and can exert both an autocrine (epithelial) and a paracrine (stromal) influence on growth. Endothelin-1 is generated from its inactive precursor big-ET-1 by endothelin-converting enzyme 1 (ECE-1). We and others have demonstrated that ECE-1 expression is significantly elevated in tumours and surrounding stromal tissue. Our current data show siRNA-mediated knockdown of stromal ECE-1 reduces epithelial (PC-3) cell invasion in coculture. Interestingly, readdition of ET-1 only partially recovers this effect suggesting a novel role for ECE-1 independent of ET-1 activation. Parallel knockdown of ECE-1 in both stromal and epithelial compartments results in an additive decrease in cell invasion. We extrapolated this observation to the four recognised isoforms ECE-1a, ECE-1b, ECE-1c and ECE-1d. Only ECE-1a and ECE-1c were significant but with reciprocal effects on cell invasion. Transient ECE-1c overexpression increased PC-3 invasiveness through matrigel, whereas transient ECE-1a expression suppressed invasion. Furthermore, transient ECE-1a expression in stromal cells strongly counteracts the effect of transient ECE-1c expression in PC-3 cells. The ECE-1 isoforms may, therefore, be relevant targets for antiinvasive therapy in prostate and other cancers

Trials

BACKGROUND: Recent data suggest that 10-20% of injury patients will suffer for several months after the event from diverse symptoms, generally referred to as post-concussion-like symptoms (PCLS), which will lead to a decline in quality of life. A preliminary randomized control trial suggested that this condition may be induced by the stress experienced during the event or emergency room (ER) stay and can be prevented in up to 75% of patients with a single, early, short eye movement desensitization and reprocessing (EMDR) psychotherapeutic session delivered in the ER. The protocol of the SOFTER 3 study was designed to compare the impact on 3-month PCLS of early EMDR intervention and usual care in patients presenting at the ER. Secondary outcomes included 3-month post-traumatic stress disorder, 12-month PCLS, self-reported stress at the ER, self-assessed recovery expectation at discharge and 3 months, and self-reported chronic pain at discharge and 3 months. METHODS: This is a two-group, open-label, multicenter, comparative, randomized controlled trial with 3- and 12-month phone follow-up for reports of persisting symptoms (PCLS and post-traumatic stress disorder). Those eligible for inclusion were adults (>/=18 years old) presenting at the ER departments of the University Hospital of Bordeaux and University Hospital of Lyon, assessed as being at high risk of PCLS using a three-item scoring rule. The intervention groups were a (1) EMDR Recent Traumatic Episode Protocol intervention performed by a trained psychologist during ER stay or (2) usual care. The number of patients to be enrolled in each group was 223 to evidence a 15% decrease in PCLS prevalence in the EMDR group. DISCUSSION: In 2012, the year of the last national survey in France, 10.6 million people attended the ER, some of whom did so several times since 18 million visits were recorded in the same year. The SOFTER 3 study therefore addresses a major public health challenge. TRIAL REGISTRATION: Clinical Trials. NCT03400813 . Registered 17 January 2018 - retrospectively registered