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

2021 ◽  
Vol 9 ◽  
Author(s):  
Abdellah Akil ◽  
Ana K. Gutiérrez-García ◽  
Rachael Guenter ◽  
J. Bart Rose ◽  
Adam W. Beck ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Progression ◽  
Notch Signaling ◽  
Cell Fate ◽  
Tumor Angiogenesis ◽  
Vascular Endothelial Cells ◽  
Notch Pathway ◽  
Vascular Endothelial ◽  
Cell Fate Determination ◽  
Fate Determination

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.

scholarly journals Vascular Notch Signaling in Stress Hematopoiesis

2021 ◽  
Vol 8 ◽  
Author(s):  
Can Huang ◽  
Dawei Yang ◽  
George W. Ye ◽  
Charles A. Powell ◽  
Peipei Guo
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Stromal Cell ◽  
Vascular Endothelial Cells ◽  
Cell Lineage ◽  
Transgenic Animals ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Hematopoietic Stem

Canonical Notch signaling is one of the most conserved signaling cascades. It regulates cell proliferation, cell differentiation, and cell fate maintenance in a variety of biological systems during development and cancer (Fortini, 2009; Kopan and Ilagan, 2009; Andersson et al., 2011; Ntziachristos et al., 2014). For the hematopoietic system, during embryonic development, Notch1 is essential for the emergence of hematopoietic stem cells (HSCs) at the aorta-gornado-mesonephro regions of the dorsal aorta. At adult stage, Notch receptors and Notch targets are expressed at different levels in diverse hematopoietic cell types and influence lineage choices. For example, Notch specifies T cell lineage over B cells. However, there has been a long-lasting debate on whether Notch signaling is required for the maintenance of adult HSCs, utilizing transgenic animals inactivating different components of the Notch signaling pathway in HSCs or niche cells. The aims of the current mini-review are to summarize the evidence that disapproves or supports such hypothesis and point at imperative questions waiting to be addressed; hence, some of the seemingly contradictory findings could be reconciled. We need to better delineate the Notch signaling events using biochemical assays to identify direct Notch targets within HSCs or niche cells in specific biological context. More importantly, we call for more elaborate studies that pertain to whether niche cell type (vascular endothelial cells or other stromal cell)-specific Notch ligands regulate the differentiation of T cells in solid tumors during the progression of T-lymphoblastic lymphoma (T-ALL) or chronic myelomonocytic leukemia (CMML). We believe that the investigation of vascular endothelial cells' or other stromal cell types' interaction with hematopoietic cells during homeostasis and stress can offer insights toward specific and effective Notch-related therapeutics.

Abstract 3380: Acetylation-dependent Regulation Of Notch1 Signaling In Endothelial Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Virginia Guarani ◽  
Franck Dequiedt ◽  
Andreas M Zeiher ◽  
Stefanie Dimmeler ◽  
Michael Potente
Keyword(s):  
Endothelial Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Trichostatin A ◽  
Notch Pathway ◽  
Dependent Manner ◽  
Class Iii ◽  
Cell Fate Decisions ◽  
Knock Down

The Notch signaling pathway is a versatile regulator of cell fate decisions and plays an essential role for embryonic and postnatal vascular development. As only modest differences in Notch pathway activity suffice to determine dramatic differences in blood vessel development, this pathway is tightly regulated by a variety of molecular mechanisms. Reversible acetylation has emerged as an important post-translational modification of several non-histone proteins, which are targeted by histone deacetylases (HDACs). Here, we report that specifically the Notch1 intracellular domain (NICD) is itself an acetylated protein and that its acetylation level is tightly regulated by the SIRT1 deacetylase, which we have previously identified as a key regulator of endothelial angiogenic functions during vascular growth. Coexpression of NICD with histone acetyltransferases such as p300 or PCAF induced a dose- and time-dependent acetylation of NICD. Blocking HDAC activity using the class III HDAC inhibitor nicotinamid (NAM), but not the class I/II HDAC inhibior trichostatin A, resulted in a significant increase of NICD acetylation suggesting that NICD is targetd by class III HDACs for deacetylation. Among the class III HDACs with deacetylase activity (SIRT1, 2, 3, 5), knock down of specifically SIRT1 resulted in enhanced acetylation of NICD. Moreover, wild type SIRT1, but not a catalytically inactive mutant catalyzed the deacetylation of NICD in a nicotinamid-dependent manner. SIRT1, but SIRT2, SIRT3 or SIRT5, associated with NICD through its catalytic domain demonstrating that SIRT1 is a direct NICD deacetylase. Enhancing NICD acetylation by either overexpression of p300 or inhibition of SIRT1 activity using NAM or RNAi-mediated knock down resulted in enhanced NICD protein stability by blocking its ubiquitin-mediated degradation. Consistent with these results, loss of SIRT1 amplified Notch target gene expression in endothelial cells in response to NICD overexpression or treatment with the Notch ligand Dll4. In summary, our results identify reversible acetylation of NICD as a novel molecular mechanism to control Notch signaling and suggest that deacetylation of NICD by SIRT1 plays a key role in the dynamic regulation of Notch signaling in endothelial cells.

scholarly journals Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

2015 ◽  
Vol 112 (5) ◽  
pp. E402-E409 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Mingyang Lu ◽  
José N. Onuchic ◽  
Cecilia Clementi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Target Genes ◽  
Tumor Stroma ◽  
Notch Receptor ◽  
Toggle Switch ◽  
Cell Fate Determination ◽  
Asymmetric Effect ◽  
Fate Determination

Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

YAP Overexpression in Breast Cancer Cells Promotes Angiogenesis Through Activating Yap Signaling in Vascular Endothelial Cells

2020 ◽  
Author(s):  
Yu Yan ◽  
Qiang Song ◽  
Li Yao ◽  
Liang Zhao ◽  
Hui Cai
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Tumor Angiogenesis ◽  
Breast Cancer Cells ◽  
Vascular Endothelial Cells ◽  
Tissue Growth ◽  
Vascular Endothelial ◽  
Potential Marker

Abstract Background:The YAP signaling pathway is altered and implicated as oncogenic in human mammary cancers.However, roles of YAP signaling that regulate the breast tumor angiogenesis have remained elusive. Tumor angiogenesis is coordinated by the activation of both cancer cells and vascular endothelial cells. Whether the YAP signalingpathway can regulate the intercellular interaction between cancer cells and endothelial cellsis essentially unknown.Results: We showed here that conditioned media from YAP overexpressed breast cancer cells (CM-YAP+) could promote angiogenesis, accompanied byincreased tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs). Down regulation of YAP in HUVECs reversed CM-YAP+ induced angiogenesis.CM-YAP+ time-dependently activated YAP inHUVECs by dephosphorylating YAP and increasing nuclear translocation.We also identified that both G13-RhoA and PI3K/Akt signaling pathway were necessary for CM-YAP+ induced activation of YAP.Besides, connective tissue growth factor (CTGF) and angiopoietin-2 (ANG-2)actedas down-stream of YAP in HUVECs to promote angiogenesis.In addition, subcutaneous tumors nude mice model demonstrated that tumors overexpressed YAP revealed moreneovascularization in vivo.Conclusions: YAP-YAP interaction between breastcancer cells and endothelial cellscould promote tumor angiogenesis, supporting that YAP is a potential marker and target fordeveloping novel therapeutic strategies against breast cancer.

Prox1 expression is negatively regulated by miR-181 in endothelial cells

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2395-2401 ◽  
Author(s):  
Jan Kazenwadel ◽  
Michael Z. Michael ◽  
Natasha L. Harvey
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Vascular Endothelial Cells ◽  
Vascular Development ◽  
Lymphatic Endothelial Cell ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
Prox1 Expression

Abstract The specification of arterial, venous, and lymphatic endothelial cell fate is critical during vascular development. Although the homeobox transcription factor, Prox1, is crucial for the specification and maintenance of lymphatic endothelial cell identity, little is known regarding the mechanisms that regulate Prox1 expression. Here we demonstrate that miR-181a binds the 3′ untranslated region of Prox1, resulting in translational inhibition and transcript degradation. Increased miR-181a activity in primary embryonic lymphatic endothelial cells resulted in substantially reduced levels of Prox1 mRNA and protein and reprogramming of lymphatic endothelial cells toward a blood vascular phenotype. Conversely, treatment of primary embryonic blood vascular endothelial cells with miR-181a antagomir resulted in increased Prox1 mRNA levels. miR-181a expression is significantly higher in embryonic blood vascular endothelial cells compared with lymphatic endothelial cells, suggesting that miR-181 activity could be an important mechanism by which Prox1 expression is silenced in the blood vasculature during development. Our work is the first example of a microRNA that targets Prox1 and has implications for the control of Prox1 expression during vascular development and neo-lymphangiogenesis.

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