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.

Development of arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic Acid/protein kinase D signaling 

“…Furthermore, the crosstalk between BCSCs and arteriolar ECs via Notch signaling may contribute to changes in CSC phenotypes 7,63,70 , in which PKD-1 signaling-mediated arteriolar differentiation may be indispensable by development of an arteriolar niche. Although distinct vascular niches are likely needed to regulate BCSCs, we found that LPA/PKD-1 signaling-mediated DLL4 expression in the arteriolar ECs facilitates direct EC interaction with Notch1 + stem-like cells.…”

“…Given that Notch1 activity plays a pivotal role in the stemness and progression of ER + BC [61][62][63] and ECs can interact with BC via the Notch1 pathway 7,63 , we tested whether PKD-1 signaling can impact Notch1 expression by transducing BC cells with PKD-1. Overexpression of PKD-1 signi cantly increased the expression of Notch1 at both mRNA and protein levels in BC cells (Figure 7C & D), along with an increased expression in CD44 and KLF4 (Figure 7E & F).…”

Circulating PTGS2, JAG1, GUCY2C and PGF mRNA in Peripheral Blood and Serum as Potential Biomarkers for Patients with Metastatic Colon Cancer

“…Crosstalk between VEGF and other signaling pathways importantly contributes to tumor angiogenesis regulation, through the activation of alternative VEGF-dependent and VEGF-independent pathways [ 34 ]. Guanylyl cyclase C (GUCY2C), a receptor member of the family of guanyl cyclases, plays an important role in regulating intracellular cGMP levels, electrolyte homeostasis and cell proliferation in the intestine [ 35 ].…”

“…Its overexpression has been associated with metastasis and poor prognosis in CRC patients [ 38 ]. On the other hand, the VEGF and Notch signaling pathways are two pivotal mechanisms in tumor angiogenesis [ 34 ]. In fact, placenta growth factor (PGF) is a ligand of the VEGF family that induces angiogenesis by both VEGF-independent and VEGF-dependent ways [ 39 ].…”

Quercetin Synergistically Potentiates the Anti-Angiogenic Effect of 5- Fluorouracil on HUVEC Cell Line

“…When tumors grow to 1-2 mm in diameter, the inner cells of the tumor become hypoxic, which inhibits the degradation of the Hypoxiainducible factor 1-alpha (HIF-1α). Hypoxia-Thus, HIF-1α is increased and binds to the Response Element (HRE) region of genes involved in angiogenesis, such as the VEGF-expressing gene, so by this way, the expression of VEGF is increased [10][11][12][13].…”