Endothelial Notch1 Activity Facilitates Metastasis

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cells, Cultured
  • Humans
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neutrophil Infiltration
  • Receptor, Notch1 / physiology*
  • Signal Transduction / physiology
  • Vascular Cell Adhesion Molecule-1 / analysis
  • Vascular Cell Adhesion Molecule-1 / physiology


  • Notch1 protein, mouse
  • Receptor, Notch1
  • Vascular Cell Adhesion Molecule-1