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.
Highlights
AA, AG-G, and RG wrote the manuscript
The activation of Notch signaling can crosstalk with numerous oncogenic signaling pathways, such as Wnt and Hedgehog signaling, cytokines, and oncogenic kinases. This crosstalk plays an important role in tumor angiogenesis and growth, invasion, metastasis, and therapeutic resistance
As a major signaling pathway in tumor progression, Notch has been extensively studied in the context of angiogenesis and CSC biology
Summary
The Notch signaling pathway is highly conserved across all vertebrate species and orchestrates a diverse range of functions including cell growth, differentiation, and patterning. In mammals, this pathway features four transmembrane receptors (Notch 1–4) that interact with five canonical transmembrane ligands (Jagged 1, 2; Delta-like ligand 1, 3, and 4) (Aquila et al, 2019). Activation of the canonical Notch pathway begins when a Notch receptor extracellularly interacts with a Notch ligand, which subsequently initiates proteolytic cleavage of the receptor This cleavage precedes two sequential proteolytic events that require the enzymes including the disintegrin metalloproteinase domain-containing protein 10 (ADAM10) and the γ-secretase. The NICD translocates to the nucleus where it acts as a transcriptional coactivator in cooperation with recombination of signal-binding protein for the immunoglobulin kappa J region (RBPJ)
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