scholarly journals Jagged mediates differences in normal and tumor angiogenesis by affecting tip-stalk fate decision

2015 ◽  
Vol 112 (29) ◽  
pp. E3836-E3844 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Eshel Ben-Jacob ◽  
José N. Onuchic
Keyword(s):  
Endothelial Cells ◽  
Cancer Progression ◽  
Wound Repair ◽  
Stalk Cell ◽  
Cell Fates ◽  
Notch Ligand ◽  
Vegf Signaling ◽  
Fate Decision ◽  
Signaling Interactions ◽  
Selection Of

Angiogenesis is critical during development, wound repair, and cancer progression. During angiogenesis, some endothelial cells adopt a tip phenotype to lead the formation of new branching vessels; the trailing stalk cells proliferate to develop the vessel. Notch and VEGF signaling mediate the selection of these tip endothelial cells. However, how Jagged, a Notch ligand that is overexpressed in cancer, affects angiogenesis remains elusive. Here, by developing a theoretical framework for Notch-Delta-Jagged-VEGF signaling, we found that higher production levels of Jagged destabilizes the tip and stalk cell fates and can give rise to a hybrid tip/stalk phenotype that leads to poorly perfused and chaotic angiogenesis, which is a hallmark of cancer. Consistently, the signaling interactions that restrict Notch-Jagged signaling, such as Fringe, cis-inhibition, and increased production of Delta, stabilize tip and stalk fates and limit the existence of hybrid tip/stalk phenotype. Our results underline how overexpression of Jagged can transform physiological angiogenesis into pathological one.

scholarly journals Harnessing Extracellular Matrix Biology for Tumor Drug Delivery

2021 ◽  
Vol 11 (2) ◽  
pp. 88
Author(s):  
Nithya Subrahmanyam ◽  
Hamidreza Ghandehari
Keyword(s):  
Drug Delivery ◽  
Extracellular Matrix ◽  
Cancer Progression ◽  
Active Role ◽  
Reciprocal Relationship ◽  
Design Parameters ◽  
Cancer Etiology ◽  
Cell Life ◽  
Tumor Drug Delivery ◽  
Signaling Interactions

The extracellular matrix (ECM) plays an active role in cell life through a tightly controlled reciprocal relationship maintained by several fibrous proteins, enzymes, receptors, and other components. It is also highly involved in cancer progression. Because of its role in cancer etiology, the ECM holds opportunities for cancer therapy on several fronts. There are targets in the tumor-associated ECM at the level of signaling molecules, enzyme expression, protein structure, receptor interactions, and others. In particular, the ECM is implicated in invasiveness of tumors through its signaling interactions with cells. By capitalizing on the biology of the tumor microenvironment and the opportunities it presents for intervention, the ECM has been investigated as a therapeutic target, to facilitate drug delivery, and as a prognostic or diagnostic marker for tumor progression and therapeutic intervention. This review summarizes the tumor ECM biology as it relates to drug delivery with emphasis on design parameters targeting the ECM.

scholarly journals Tetranectin Binds to the Kringle 1-4 Form of Angiostatin and Modifies Its Functional Activity

2004 ◽  
Vol 2004 (2) ◽  
pp. 73-78 ◽  
Author(s):  
Tirsit Mogues ◽  
Michael Etzerodt ◽  
Crystal Hall ◽  
Georg Engelich ◽  
Jonas H. Graversen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cancer Progression ◽  
Functional Activity ◽  
Binding Protein ◽  
Antiproliferative Activities

Tetranectin is a plasminogen kringle 4 domain-binding protein present in plasma and various tissue locations. Decreased plasma tetranectin or increased tetranectin in stroma of cancers correlates with cancer progression and adverse prognosis. A possible mechanism through which tetranectin could influence cancer progression is by altering activities of plasminogen or the plasminogen fragment, angiostatin. Tetranectin was found to bind to the kringle 1-4 form of angiostatin (ASTK1-4). In addition, tetranectin inhibited binding of plasminogen or ASTK1-4to extracellular matrix (ECM) deposited by endothelial cells. Finally, tetranectin partially counteracted the ability of ASTK1-4to inhibit proliferation of endothelial cells. This latter effect of tetranectin was specific for ASTK1-4since it did not counteract the antiproliferative activities of the kringle 1-3 form of angiostatin (ASTK1-3) or endostatin. These findings suggest that tetranectin may modulate angiogenesis through interactions with AST.

scholarly journals Stromal Endothelial Cells Directly Influence Cancer Progression

2011 ◽  
Vol 3 (66) ◽  
pp. 66ra5-66ra5 ◽  
Author(s):  
J. W. Franses ◽  
A. B. Baker ◽  
V. C. Chitalia ◽  
E. R. Edelman
Keyword(s):  
Endothelial Cells ◽  
Cancer Progression

Abstract 117: RhoC Regulates VEGF-induced Signaling in Endothelial Cells

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Luke Hoeppner ◽  
Sutapa Sinha ◽  
Ying Wang ◽  
Resham Bhattacharya ◽  
Shamit Dutta ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Permeability ◽  
Rho Gtpase ◽  
Endothelial Cell Migration ◽  
Calcium Flux ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vegf Signaling

Vascular permeability factor/vascular endothelial growth factor A (VEGF) is a central regulator of angiogenesis and potently promotes vascular permeability. VEGF plays a key role in the pathologies of heart disease, stroke, and cancer. Therefore, understanding the molecular regulation of VEGF signaling is an important pursuit. Rho GTPase proteins play various roles in vasculogenesis and angiogenesis. While the functions of RhoA and RhoB in these processes have been well defined, little is known about the role of RhoC in VEGF-mediated signaling in endothelial cells and vascular development. Here, we describe how RhoC modulates VEGF signaling to regulate endothelial cell proliferation, migration and permeability. We found VEGF stimulation activates RhoC in human umbilical vein endothelial cells (HUVECs), which was completely blocked after VEGF receptor 2 (VEGFR-2) knockdown indicating that VEGF activates RhoC through VEGFR-2 signaling. Interestingly, RhoC knockdown delayed the degradation of VEGFR-2 compared to control siRNA treated HUVECs, thus implicating RhoC in VEGFR-2 trafficking. In light of our results suggesting VEGF activates RhoC through VEGFR-2, we sought to determine whether RhoC regulates vascular permeability through the VEGFR-2/phospholipase Cγ (PLCγ) /Ca 2+ /eNOS cascade. We found RhoC knockdown in VEGF-stimulated HUVECs significantly increased PLC-γ1 phosphorylation at tyrosine 783, promoted basal and VEGF-stimulated eNOS phophorylation at serine 1177, and increased calcium flux compared with control siRNA transfected HUVECs. Taken together, our findings suggest RhoC negatively regulates VEGF-induced vascular permeability. We confirmed this finding through a VEGF-inducible zebrafish model of vascular permeability by observing significantly greater vascular permeability in RhoC morpholino (MO)-injected zebrafish than control MO-injected zebrafish. Furthermore, we showed that RhoC promotes endothelial cell proliferation and negatively regulates endothelial cell migration. Our data suggests a scenario in which RhoC promotes proliferation by upregulating -catenin in a Wnt signaling-independent manner, which in turn, promotes Cyclin D1 expression and subsequently drives cell cycle progression.

A Fibrous Hybrid Patch Couples Cell-Derived Matrix and Poly(l-lactide-co-caprolactone) for Endothelial Cells Delivery and Skin Wound Repair

2018 ◽  
Vol 5 (2) ◽  
pp. 900-910 ◽  
Author(s):  
Ping Du ◽  
Cininta Casavitri ◽  
Muhammad Suhaeri ◽  
Peng-Yuan Wang ◽  
Jong Ho Lee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Wound Repair ◽  
Skin Wound

scholarly journals Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

2015 ◽  
Vol 17 ◽  
Author(s):  
Esak Lee ◽  
Niranjan B. Pandey ◽  
Aleksander S. Popel
Keyword(s):  
Endothelial Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Malignant Cell ◽  
Lymphatic Endothelial Cells ◽  
Tumour Blood

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.

scholarly journals Adenosine triphosphate is a critical determinant for VEGFR signal during hypoxia

2016 ◽  
Vol 311 (6) ◽  
pp. C985-C995 ◽  
Author(s):  
Abdullah Al Mamun ◽  
Hisaki Hayashi ◽  
Miho Sakima ◽  
Motohiko Sato
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Signal Propagation ◽  
Tube Formation ◽  
Activation Process ◽  
Vegf Receptor ◽  
Vegf Mrna ◽  
Critical Determinant ◽  
Hypoxia Exposure ◽  
Vegf Signaling

Hypoxia induces angiogenesis through the VEGF signaling pathway; however, signal propagation of VEGF in hypoxia is not fully understood. In this study, we examined alterations in VEGF signaling during hypoxia conditions and its determinant in endothelial cells. To analyze VEGF signaling during hypoxia, human umbilical vein endothelial cells (HUVECs) were exposed to 3 h of hypoxia (1% O2) followed by 3 h of reoxygenation or 12 h of hypoxia. Hypoxia induced expression of VEGF mRNA, but it was not associated with an increase in tube formation by HUVECs. During 3 h of hypoxia, VEGF-induced phosphorylation of VEGF receptor-2 (VEGFR-2) and downstream molecules were significantly inhibited without a change in VEGFR-2 expression, but it was completely restored after reoxygenation. VEGF-mediated VEGFR-2 phosphorylation is associated with a reduction in cellular ATP in hypoxia conditions (65.93 ± 8.32% of normoxia, means ± SE, P < 0.01). Interestingly, attenuation of VEGFR-2 phosphorylation was restored by addition of ATP to prepared membranes from cells that underwent 3 h of hypoxia. In contrast to 3 h of hypoxia, exposure of cells to 12 h of hypoxia decreased VEGFR-2 expression and VEGF-mediated VEGFR-2 phosphorylation. The magnitude of VEGFR-2 phosphorylation was not fully restored by addition of ATP to prepared membranes from cells exposed to 12 h of hypoxia. These data indicate that ATP is an important determinant of VEGF signaling in hypoxia and suggest that the activation process of VEGFR-2 was modified by sustained hypoxia. These observations contribute to our understanding of signal alterations in VEGF in endothelial cells during hypoxia.

Sign in / Sign up

Export Citation Format

Share Document