TY - JOUR
T1 - Endothelial Notch1 Activity Facilitates Metastasis
AU - Wieland, Elfriede
AU - Rodriguez-Vita, Juan
AU - Liebler, Sven S.
AU - Mogler, Carolin
AU - Moll, Iris
AU - Herberich, Stefanie E.
AU - Espinet, Elisa
AU - Herpel, Esther
AU - Menuchin, Amitai
AU - Chang-Claude, Jenny
AU - Hoffmeister, Michael
AU - Gebhardt, Christoffer
AU - Brenner, Hermann
AU - Trumpp, Andreas
AU - Siebel, Christian W.
AU - Hecker, Markus
AU - Utikal, Jochen
AU - Sprinzak, David
AU - Fischer, Andreas
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/3/13
Y1 - 2017/3/13
N2 - 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.
AB - 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.
KW - Notch signaling
KW - angiogenesis
KW - endothelial cell
KW - extravasation
KW - intravasation
KW - metastasis
KW - mouse models
KW - neutrophils
KW - senescence
KW - vascular biology
UR - http://www.scopus.com/inward/record.url?scp=85013625323&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2017.01.007
DO - 10.1016/j.ccell.2017.01.007
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AN - SCOPUS:85013625323
SN - 1535-6108
VL - 31
SP - 355
EP - 367
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -