作者
Jacqueline Taylor,Leonie Uhl,Iris Moll,Sana S. Hasan,Lena Wiedmann,Jakob Morgenstern,Benedetto Daniele Giaimo,Tobias Friedrich,Elisenda Alsina‐Sanchís,Francesca Rigotti,Ronja Mülfarth,Sarah Kaltenbach,Darius Schenk,Felix Nickel,Gernot Poschet,David Sprinzak,Carolin Mogler,Thomas Korff,Adrian T. Billeter,Beat P. Müller‐Stich,Mauricio Berriel Díaz,Tilman Borggrefe,Stephan Herzig,Maria Rohm,Juan Rodríguez‐Vita,Andreas Fischer
摘要
Abstract Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.