Σάββατο, 25 Φεβρουαρίου 2017

Endothelial Notch1 Activity Facilitates Metastasis

Publication date: Available online 23 February 2017
Source:Cancer Cell
Author(s): Elfriede Wieland, Juan Rodriguez-Vita, Sven S. Liebler, Carolin Mogler, Iris Moll, Stefanie E. Herberich, Elisa Espinet, Esther Herpel, Amitai Menuchin, Jenny Chang-Claude, Michael Hoffmeister, Christoffer Gebhardt, Hermann Brenner, Andreas Trumpp, Christian W. Siebel, Markus Hecker, Jochen Utikal, David Sprinzak, Andreas Fischer
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.

Graphical abstract

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Teaser

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.


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