Notch Signaling in Vascular Endothelial Cells, Angiogenesis, and Tumor Progression: An Update and Prospective

Abstract

The Notch signaling pathway plays an essential role in a wide variety of biological processes including cell fate determination of vascular endothelial cells and the regulation of arterial differentiation and angiogenesis. The Notch pathway is also an essential regulator of tumor growth and survival by functioning as either an oncogene or a tumor suppressor in a context-dependent manner. Crosstalk between the Notch and other signaling pathways is also pivotal in tumor progression by promoting cancer cell growth, migration, invasion, metastasis, tumor angiogenesis, and the expansion of cancer stem cells (CSCs). In this review, we provide an overview and update of Notch signaling in endothelial cell fate determination and functioning, angiogenesis, and tumor progression, particularly in the development of CSCs and therapeutic resistance. We further summarize recent studies on how endothelial signaling crosstalk with the Notch pathway contributes to tumor angiogenesis and the development of CSCs, thereby providing insights into vascular biology within the tumor microenvironment and tumor progression.

Keywords: Notch signaling; angiogenesis; arteriolar niche; cancer stem cell; tumor microenvironment.

FIGURE 1

Overview of the Notch signaling pathway. Binding of the Notch ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1 and Jagged 2) to the transmembrane Notch receptors (Notch 1–4) results in proteolytic cleavage events by ADAM and γ-secretase to mediate the release of the Notch intracellular domain (NICD). The NICD then enters the nucleus and interacts with cofactors to regulate the expression of target genes involved in EndoMT, angiogenesis, and CSC biology.

FIGURE 2

Schematic models of Notch signaling in vascular endothelial cell (EC) differentiation. (A) In endothelial tip cells, VEGF signaling induces DLL4 expression, which activates Notch1 signaling. In endothelial stalk cells, activation of Notch signaling via DLL4 suppresses differentiation toward a tip cell phenotype. (B) Graphic representation of lateral inhibition to show a classical salt and pepper pattern where tip cells are separated exactly by one stalk cell. DLL4 of one cell binds to the Notch receptor of the adjacent cell, and Notch inhibits DLL4 expression and the VEGFR2 signaling within the same cell. (C) Mathematic model of Notch signaling in asymmetric patterning. Cells do not necessarily adopt a canonical salt and pepper pattern. Instead, two tip cells might be separated by a few stalk cells, which could be determined by Jag. It is also possible that an intermediary tip cell may express similar DLL4 and Notch expression. Both theories involve a third EC state.

FIGURE 3

Notch signaling regulates endothelial to mesenchymal transition. (A) Notch signaling induces an endothelial to mesenchymal transition (EndoMT). As an example, active NICD regulates the expression of Snail1, a key EndoMT transcription factor to promote EndoMT. (B) Partial EndoMT, where cells temporarily lose apical-basal polarity and gain migratory capacity, while retaining intercellular junctions and undergoing collective rather than individualized cell migration.

FIGURE 4

Diverse involvement of Notch signaling in angiogenesis and CSCs. The interaction between VEGF and DLL4/Notch signaling regulates angiogenesis. In addition, active Notch signaling can promote the development of the CSC phenotype, the renewal and plasticity of CSCs, and promote an epithelial to mesenchymal transition (EMT).