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Cancer Cell. 2017 Mar 13;31(3):355-367. doi: 10.1016/j.ccell.2017.01.007. Epub 2017 Feb 23.

Endothelial Notch1 Activity Facilitates Metastasis.

Author information

1
Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Vascular Biology, CBTM, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
3
Institute of Pathology, Heidelberg University Hospital, Vascular Oncology and Metastasis (A190), German Cancer Research Center, 69120 Heidelberg, Germany.
4
Division of Stem Cells and Cancer (A010), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance and the German Cancer Consortium (DKTK), Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
5
Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
6
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, 69978 Tel Aviv, Israel.
7
Division of Cancer Epidemiology (C020), German Cancer Research Center, 69120 Heidelberg, Germany; Research Group Genetic Cancer Epidemiology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
8
Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
9
Clinical Cooperation Unit Dermato-Oncology (G300), German Cancer Research Center (DKFZ), Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 69120 Heidelberg, Germany.
10
Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Division of Preventive Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
11
Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
12
Department of Cardiovascular Physiology, Heidelberg University and Deutsches Zentrum für Herz-Kreislauf-Forschung e.V. (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
13
Vascular Signaling and Cancer (A270), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Vascular Biology, CBTM, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; Department of Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120 Heidelberg, Germany. Electronic address: a.fischer@dkfz.de.

Abstract

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.

KEYWORDS:

Notch signaling; angiogenesis; endothelial cell; extravasation; intravasation; metastasis; mouse models; neutrophils; senescence; vascular biology

PMID:
28238683
DOI:
10.1016/j.ccell.2017.01.007
[Indexed for MEDLINE]
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