scholarly journals The Metastatic Capacity of Melanoma Reveals Alternative Pathways of Cancer Dissemination

2021 ◽  
Vol 1 (3) ◽  
pp. 163-174
Author(s):  
Michela Corsini ◽  
Cosetta Ravelli ◽  
Elisabetta Grillo ◽  
Stefania Mitola
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Cancer Cells ◽  
Cell Activity ◽  
Tumor Vascularization ◽  
Tumor Mass ◽  
Alternative Pathways ◽  
Metastatic Capacity ◽  
Cancer Dissemination

For many years the growth of solid tumors has been associated with their vascularization. The new vessels are needed to deliver oxygen and nutrients within the tumor mass. At the same time, these poorly stabilized vessels act as “Trojan horses” and open a way out for cancer cells. More recently, tumors have been identified whose growth appears to be independent of endothelial cell activity. Here we describe the ability of cancer cells to differentiate and reorganize themself in channels similar to blood vessels containing blood flow, overcoming the need for the angiogenic process of tumor vascularization. Together with the new vessels arising both from angiogenic and vasculogenic processes, these vessel-like structures can be exploited by tumor cells as a guide for migration and metastatic dissemination. In addition to classical intravascular dissemination, cancer cells can acquire pericytic features, interact with the endothelial basal lamina and migrate toward vessels or outside of the vessels. As expected, these alternative tumor behaviors assume greater importance if we consider that drugs with anti-angiogenic action directed against endothelial cells or their ligands are currently used in cancer therapy.

Abstract 555: Bone Morphogenetic Protein Modulator BMPER Induces Angiogenesis via Inhibition of Thrombospondin-1 and Activation of the Fibroblast Growth Factor Signaling Pathway

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jennifer S Esser ◽  
Susanne Rahner ◽  
Meike Deckler ◽  
Christoph Bode ◽  
Martin Moser
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Cell Activity ◽  
Dependent Manner ◽  
Fgf Signaling ◽  
Endothelial Cell Function ◽  
Angiogenic Activity ◽  
Thrombospondin 1

Introduction: Bone morphogenetic proteins (BMP) play a key role in vascular development. Previously, we have identified BMP endothelial cell precursor-derived regulator (BMPER), an extracellular BMP modulator, to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project we now investigate how the BMPER effect is mediated by key molecules of angiogenesis. Methods and Results: To assess the effect of BMPER on angiogenesis-related molecules we performed an angiogenesis antibody array with BMPER-stimulated human umbilical venous endothelial cells (HUVECs) and vice versa with BMPER-silenced HUVECs compared to control conditions, respectively. We detected increased protein expression of the anti-angiogenic thrombospondin-1 (TSP-1) 48 hours after siBMPER transfection and, consistently, decreased TSP-1 expression after stimulation with BMPER (60 ng/ml; 39% ± 7.3 N=4). Furthermore, the pro-angiogenic protein bFGF was increased after BMPER stimulation, which was confirmed by realtime-PCR and western blot analysis (288.8% ± 74.8 N=3). Additionally, we detected increased FGF receptor-1 protein expression (137.7% ± 0.4 N=3) as well as FGF signaling pathway activation. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased HUVEC angiogenic activity in matrigel, migration and spheroid assays and concomitant inhibition of FGF signaling by an anti-bFGF antibody effectively inhibited the pro-angiogenic BMPER effect. Silencing of BMPER decreased the expression of FGFR1 and, accordingly, stimulation of BMPER-silenced cells with bFGF showed decreased angiogenic endothelial cell activity (65%) compared to control. The angiogenic activity of bFGF was also reduced in C57BL/6_Bmper +/- mice as assessed in the matrigel plug assay. Ex vivo aortic ring assays of C57BL/6_Bmper +/- mice confirmed a specific effect for bFGF but not for VEGF. Conclusion: In summary, BMPER inhibits the expression of the anti-angiogenic TSP-1 and increased the expression as well as activation of the pro-angiogenic FGF signaling pathway, which overall lead to the promotion of angiogenesis.

scholarly journals Alternative Strategies to Inhibit Tumor Vascularization

2019 ◽  
Vol 20 (24) ◽  
pp. 6180 ◽  
Author(s):  
Alessia Brossa ◽  
Lola Buono ◽  
Sofia Fallo ◽  
Alessandra Fiorio Pla ◽  
Luca Munaron ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tumor Microenvironment ◽  
Tumor Vasculature ◽  
Cell Phenotype ◽  
Tumor Vascularization ◽  
Alternative Strategies ◽  
Tumor Endothelial Cells ◽  
Alternative Approach ◽  
Different Origin

Endothelial cells present in tumors show different origin, phenotype, and genotype with respect to the normal counterpart. Various mechanisms of intra-tumor vasculogenesis sustain the complexity of tumor vasculature, which can be further modified by signals deriving from the tumor microenvironment. As a result, resistance to anti-VEGF therapy and activation of compensatory pathways remain a challenge in the treatment of cancer patients, revealing the need to explore alternative strategies to the classical anti-angiogenic drugs. In this review, we will describe some alternative strategies to inhibit tumor vascularization, including targeting of antigens and signaling pathways overexpressed by tumor endothelial cells, the development of endothelial vaccinations, and the use of extracellular vesicles. In addition, anti-angiogenic drugs with normalizing effects on tumor vessels will be discussed. Finally, we will present the concept of endothelial demesenchymalization as an alternative approach to restore normal endothelial cell phenotype.

scholarly journals Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events

2008 ◽  
Vol 205 (2) ◽  
pp. 373-383 ◽  
Author(s):  
Adam E. Mullick ◽  
Katrin Soldau ◽  
William B. Kiosses ◽  
Thomas A. Bell ◽  
Peter S. Tobias ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Lipid Accumulation ◽  
Laser Scanning ◽  
Cell Injury ◽  
Tlr2 Expression ◽  
Endothelial Cell Injury ◽  
Leukocyte Accumulation ◽  
Lesser Curvature

Toll-like receptors (TLRs) are pattern recognition receptors of innate immunity. TLRs initiate inflammatory pathways that may exacerbate chronic inflammatory diseases like atherosclerosis. En face laser scanning confocal microscopy (LSCM) of isolated aortic segments revealed the distribution of intimal TLR2 expression and the atheroprotective outcomes resulting from a TLR2 deficiency. TLR2 expression was restricted to endothelial cells in regions of disturbed blood flow, such as the lesser curvature region, in atherosclerosis-prone, low-density lipoprotein receptor–deficient (LDLr−/−) mice. Diet-induced hyperlipidemia in LDLr−/− mice increased this regional endothelial TLR2 expression. Bone marrow (BM) reconstitution of LDLr−/− and LDLr−/−TLR2−/− mice created chimeric mice with green fluorescent protein (GFP) expression in BM-derived cells (BMGFP+). Lesser curvature BMGFP+ leukocyte accumulation, lipid accumulation, foam cell generation and endothelial cell injury were all increased by hyperlipidemia, whereas hyperlipidemic double mutant BMGFP+LDLr−/−TLR2−/− mice had reduced BMGFP+ leukocyte accumulation, lipid accumulation, foam cells, and endothelial cell injury. This is the first report of in vivo site-specific expression of endothelial cell TLR2. Expression of this receptor on endothelial cells contributed to early atherosclerotic processes in lesion-prone areas of the mouse aorta.

Revealing anti-inflammatory mechanisms of soy isoflavones by flow: modulation of leukocyte-endothelial cell interactions

2005 ◽  
Vol 289 (2) ◽  
pp. H908-H915 ◽  
Author(s):  
Balu K. Chacko ◽  
Robert T. Chandler ◽  
Ameya Mundhekar ◽  
Nicholas Khoo ◽  
Heather M. Pruitt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Principal Component ◽  
Vascular Endothelial ◽  
Physical Forces ◽  
Anti Inflammatory ◽  
Static Conditions

The antiatherogenic effects of soy isoflavone consumption have been demonstrated in a variety of studies. However, the mechanisms involved remain poorly defined. Adhesion of monocytes to vascular endothelial cells is a key step within the inflammatory cascade that leads to atherogenesis. Many factors, including the physical forces associated with blood flow, regulate this process. Using an in vitro flow assay, we report that genistein, a principal component of most isoflavone preparations, inhibits monocyte adhesion to cytokine (TNF-α)-stimulated human vascular endothelial cells at physiologically relevant concentrations (0–1 μM). This effect is absolutely dependent on flow and is not observed under static conditions. Furthermore, this inhibition was dependent on activation of endothelial peroxisomal proliferator-activated receptor-γ. No significant role for other reported properties of genistein, including antioxidant effects, inhibition of tyrosine kinases, or activation of estrogen receptors, was observed. Furthermore, the antiadhesive effects of genistein did not occur via modulation of the adhesion molecules E-selectin, ICAM-1, VCAM-1, or platelet-endothelial cell adhesion molecule-1. These data reveal a novel anti-inflammatory mechanism for isoflavones and identify the physical forces associated with blood flow and a critical mediator of this function.

Vascular Endothelial Morphology as an Indicator of the Pattern of Blood Flow

1981 ◽  
Vol 103 (3) ◽  
pp. 172-176 ◽  
Author(s):  
R. M. Nerem ◽  
M. J. Levesque ◽  
J. F. Cornhill
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Cell Morphology ◽  
Flow Direction ◽  
Rabbit Aorta ◽  
Shape Index ◽  
En Face ◽  
Length Width ◽  
Branch Vessel

A quantitative study of the en face size and shape of endothelial cells from aortic intercostal ostia has been carried out in rabbits. Photomicrographs were taken from vascular casts of the rabbit aorta and the endothelial cell outlines were analyzed quantitatively using a digitizer and digital computer. The morphology of the endothelial cells was described using 8 calculated parameters (area, perimeter, length, width, angle of orientation, width: length ratio, axis-intersection ratio and shape index). Marked changes in cell morphology were found in the regions proximal and distal to ostia as well as around flow dividers. Cells on the aorta are aligned with the flow direction, and the endothelial cells within the ostia have an angle of orientation of approximately 45 deg to the axis of the vessel. The results obtained to date suggest that endothelial cell morphology and orientation around a branch vessel may be a natural marker or indicator of the detailed features of blood flow.

Endothelial Cell Permeability and Alignment Quantification Under Shear Flow

2010 ◽  
Author(s):  
Lucas Ting ◽  
Jessica Jahn ◽  
Nathan Sniadecki
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Cardiac Event ◽  
Cell Permeability ◽  
Endothelial Barrier ◽  
Mechanical Factor ◽  
Cellular Mechanotransduction ◽  
Endothelial Cell Permeability ◽  
Flow Through

Atherosclerosis develops when a breach in the protective endothelium allows macrophages and fatty lipids to enter into the intima. Atherosclerotic plaque material can harden the vessel or constrict blood flow through the vessel. In some cases, the plaque can detach and initiate a cardiac event (1). Hemodynamic shear can act as a mechanical factor that regulates the endothelial barrier by initiating a cellular mechanotransduction response that remodels the structure of individual endothelial cells (2).

scholarly journals Selective Requirements for Vascular Endothelial Cells and Circulating Factors in the Regulation of Retinal Neurogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Susov Dhakal ◽  
Shahar Rotem-Bamberger ◽  
Josilyn R. Sejd ◽  
Meyrav Sebbagh ◽  
Nathan Ronin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Endothelial Cell ◽  
Cell Differentiation ◽  
Gas Exchange ◽  
Vascular System ◽  
Vascular Endothelial Cells ◽  
Retinal Development ◽  
Vascular Endothelial ◽  
Vertebrate Eye

Development of the vertebrate eye requires signaling interactions between neural and non-neural tissues. Interactions between components of the vascular system and the developing neural retina have been difficult to decipher, however, due to the challenges of untangling these interactions from the roles of the vasculature in gas exchange. Here we use the embryonic zebrafish, which is not yet reliant upon hemoglobin-mediated oxygen transport, together with genetic strategies for (1) temporally-selective depletion of vascular endothelial cells, (2) elimination of blood flow through the circulation, and (3) elimination of cells of the erythroid lineage, including erythrocytes. The retinal phenotypes in these genetic systems were not identical, with endothelial cell-depleted retinas displaying laminar disorganization, cell death, reduced proliferation, and reduced cell differentiation. In contrast, the lack of blood flow resulted in a milder retinal phenotype showing reduced proliferation and reduced cell differentiation, indicating that an endothelial cell-derived factor(s) is/are required for laminar organization and cell survival. The lack of erythrocytes did not result in an obvious retinal phenotype, confirming that defects in retinal development that result from vascular manipulations are not due to poor gas exchange. These findings underscore the importance of the cardiovascular system supporting and controlling retinal development in ways other than supplying oxygen. In addition, these findings identify a key developmental window for these interactions and point to distinct functions for vascular endothelial cells vs. circulating factors.

scholarly journals Influence of VEGF deprivation upon vascular formation by endothelium in the presence of macrophages

2020 ◽  
Vol 22 (2) ◽  
pp. 231-248
Author(s):  
A. R. Kozyreva ◽  
T. Yu. Lvova ◽  
K. L. Markova ◽  
A. S. Simbirtsev ◽  
A. M. Ischenko ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Monoclonal Antibodies ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Blood Vessels ◽  
Cell Activity ◽  
Vegf Receptors ◽  
Contact Interactions ◽  
Functional Load

Development of angiogenesis depends on the functional state of endothelial cells, as well as on the balanced secretion of cytokines, growth factors and chemokines by endothelial cells and cells of microenvironment. Macrophages represent an essential component of the microenvironment and take part in the formation of blood vessels both due to the production of cytokines and due to contact interactions with endothelial cells. VEGF is among the most important cytokines that control angiogenesis at all its stages. Currently, the role of VEGF in the intercellular interactions of endothelial cells and macrophages is not well described. The aim of our study was to investigate the effect of VEGF deprivation using monoclonal antibodies on angiogenesis under conditions of co-cultivation of endothelium and macrophages. Materials and methods: monoclonal antibodies to VEGF-A were used for VEGF deprivation in monoculture of endothelial cells and in co-culture of endothelial cells with macrophages. The IL-1β, IL-6 and TNFα cytokines were used as inducers. When VEGF-A was removed from the medium, endothelial cells show plasticity and form longer vessels, they modify the expression of VEGF receptors. Macrophages regulate endothelial cell activity through the secretion of cytokines, including VEGF, and through contact interactions with endothelial cells. THP-1 cells increase the sensitivity of endothelial cells to VEGF by stimulating the VEGFR1 and VEGFR3 expression, this effect is VEGF-A-independent. The IL-1β, IL-6, TNFa cytokines independently stimulate non-branching angiogenesis, increasing the length of the vessels. At the same time, IL-ip increases the VEGFR1 expression on the surface of endothelial cells. In contrast, IL-6 and TNFα decrease it, thereby regulating the sensitivity of endothelial cells to VEGF. The effects of these cytokines are not dependent on VEGF-A. The IL-1β, IL-6, TNFα cytokines promote acquisition of anti-angiogenic properties by THP-1 cells that is independent on VEGF-A, as well as on expression of its receptors by endothelial cells. Thus, VEGF is an important, but not the sole factor controlling angiogenesis. Under conditions of VEGF-A deficiency, either endothelial cells or microenvironment cells are able to compensate for its functional load due to the production of other growth factors.

Shear type and magnitude affect aortic valve endothelial cell morphology, orientation, and differentiation

2021 ◽  
pp. 153537022110233
Author(s):  
Nandini Deb ◽  
Mir S Ali ◽  
Ashley Mathews ◽  
Ya-Wen Chang ◽  
Carla MR Lacerda
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Shear Stress ◽  
Endothelial Cell ◽  
Heart Valves ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Different Types ◽  
Mesenchymal Transformation

Valvular endothelial cells line the outer layer of heart valves and can withstand shear forces caused by blood flow. In contrast to vascular endothelial cells, there is limited amount of research over valvular endothelial cells. For this reason, the exact physiologic behavior of valvular endothelial cells is unclear. Prior studies have concluded that valvular endothelial cells align perpendicularly to the direction of blood flow, while vascular endothelial cells align parallel to blood flow. Other studies have suggested that different ranges of shear stress uniquely impact the behavior of valvular endothelial cells. The goal of this study was to characterize the response of valvular endothelial cell under different types, magnitudes, and durations of shear stress. In this work, the results demonstrated that with increased shear rate and duration of exposure, valvular endothelial cells no longer possessed the traditional cuboidal morphology. Instead through the change in cell circularity and aspect ratio, valvular endothelial cells aligned in an organized manner. In addition, different forms of shear exposure caused the area and circularity of valvular endothelial cells to decrease while inducing mesenchymal transformation validated through αSMA and TGFβ1 expression. This is the first investigation showing that valvular endothelial cells alignment is not as straightforward as once thought (perpendicular to flow). Different types and magnitudes of shear induce different local behaviors. This is also the first demonstration of valvular endothelial cells undergoing EndMT without chemical inducers on a soft surface in vitro. Findings from this study provide insights to understanding the pathophysiology of valvular endothelial cells which can potentially propel future artificial engineered heart valves.

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