Details

Autor(en) / Beteiligte

• Wieland, Elfriede
• Rodriguez-Vita, Juan
• Liebler, Sven S.
• Mogler, Carolin
• Moll, Iris
• Herberich, Stefanie E.
• Espinet, Elisa
• Herpel, Esther
• Menuchin, Amitai
• Chang-Claude, Jenny
• Hoffmeister, Michael
• Gebhardt, Christoffer
• Brenner, Hermann
• Trumpp, Andreas
• Siebel, Christian W.
• Hecker, Markus
• Utikal, Jochen
• Sprinzak, David
• Fischer, Andreas

Titel

Endothelial Notch1 Activity Facilitates Metastasis

Ist Teil von

• Cancer cell, 2017-03, Vol.31 (3), p.355-367

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model. [Display omitted] •Tumor ECs frequently have activated Notch1 and this correlates with poor prognosis•Sustained EC Notch1 activity promotes TC migration across the vessel wall•Endothelial Notch1 hyperactivation promotes neutrophil infiltration and metastasis•Neutrophil infiltration and metastasis depend on Notch1-induced VCAM1 expression Wieland, Rodriguez-Vita et al. reveal that activated Notch1 signaling in endothelial cells (ECs) in tumors and in the pre-metastatic niche induces VCAM1 expression, leading to increased neutrophil infiltration and metastasis. Inhibition of Notch1 or VCAM1 reduces metastasis driven by EC Notch1 in mouse models.