Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts

Rezaei, Maryam; Cavaco, Ana M.; Stehling, Martin; Nottebaum, Astrid F.; Brockhaus, Katrin; Caliandro, Michele F.; Schelhaas, Sonja; Schmalbein, Felix; Vestweber, Dietmar; Eble, Johannes A.

doi:10.3390/cancers12082138

Cited by 20 publications

(19 citation statements)

References 55 publications

(58 reference statements)

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“…VE-cadherin belongs to the calcium-dependent adhesin family and is mainly expressed at the adhesion sites of endothelial cells. It plays an important role in endothelial cell migration and survival, angiogenesis, and maintenance of vascular integrity ( Rezaei et al, 2020 ). Studies have found that VE-cadherin enhances the VM ability of liver cancer cells ( Shuai et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis

et al. 2021

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New strategies and drugs are urgently needed to improve the treatment of hepatocellular carcinoma (HCC). Vasculogenic mimicry (VM) has been elucidated being associated with the progression of HCC and anti-VM could be a promising strategy. Celastrus orbiculatus extract (COE), a mixture of 26 compounds isolated from the Chinese Herb Celastrus Orbiculatus Vine, has been elucidated to be able to disrupt VM formation in HCC. This study aims to dissect and identify the potential targets of COE on anti-VM formation both in vitro and in vivo that are distinct from our previous study. Proteomics analysis was used to identify differential proteins in HCC cells treated with or without COE (Data are available via ProteomeXchange with identifier PXD022203). Cells invasion was examined using Transwell. Matrigel was used to establish a 3-D culture condition for VM formation in vitro. RT-PCR and Western Blot were used to examine changes of mRNA and protein respectively. Clinical resected samples were applied to confirm association between VM formation and identified targets. Subcutaneous xenograft tumor model was established to observe tumor growth and VM formation in vivo. PAS-CD34 dual staining was used to detect VM in vivo. A total of 194 proteins were identified to be differentially expressed in HCC cells treated with or without COE. In the 93 down-regulated proteins EphA2 stood out to be regulated on both RNA and protein level. Disruption EphA2 using COE or NVP inhibited VM formation and decreased VM associated biomarkers. In xenograft mouse model, COE inhibited tumor growth and VM formation via down-regulating EphA2. Taken together, our results indicate that COE could be used in HCC treatment because of its promising anti-VM effect.

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Section: Discussionmentioning

confidence: 99%

COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis

et al. 2021

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“…[6,34] Moreover, the hydrogel is acting as a 3D microenvironment which can give essential stimuli to cultivated cells. [7] An additional advantage has been shown in the field of studying cell-cell interactions [4] as the co-encapsulation of cell types results in a close co-localization for studying their isolated interaction. Cell-laden hydrogel beads represent a porous and diffusable system that is ideal for implementing staining procedures.…”

Section: Discussionmentioning

confidence: 99%

“…Microfluidic systems have been used in several eukaryotic cell culture applications such as analyzing tumor organoids, [1,2] cell-cell interactions, [3,4] single-cell immune dynamics, [5] and the analysis of stem cell behavior including differentiation studies [6,7] but also for the single-cell culture of prokaryotes. [8][9][10] Although these studies show the potential of microfluidics for cell culture applications, microfluidic procedures are still difficult to implement in biological laboratories without intensive investments into equipment and personal resources.…”

Section: Introductionmentioning

confidence: 99%

A Macro‐to‐Micro Interface for Performing Comprehensive Microfluidic Cell Culture Assays

Kleine‐Brüggeney¹,

Weingarten²,

Bockeloh³

et al. 2021

Adv Materials Inter

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conditions, complicated handling due to a large number of tubing connections, and the lack of compatibility with established laboratory infrastructure and bioassays. Performing experiments in desired cell culture microenvironments (2D or 3D model) possesses another additional challenge. The physiological relevance of a 3D microenvironment has been extensively studied elsewhere. [11,12] Recent studies show that, especially for clinically relevant processes, 2D cell culture systems have limitations as they result in abnormal phenotypes. [13] In addition to the biological issues, major technical hurdles exist with 2D cultivation in available microfluidic devices. These hurdles include immobilization of non-adherent cells such as cells derived from the hematopoietic system to prevent cell loss during medium exchange and detaching adherent cells from the chip for downstream analysis. Both procedures can substantially alter the inherent cell phenotype. [14,15] In comparison, 3D cell culture models gained significant relevance in the past years due to their biocompatibility, tissue like water content, high porosity, permeability, and in mimicking mechanical properties of the extracellular matrix resulting in a higher physiological relevance. [16] Despite its biological advantages, 3D cell culture hampers the combination of time-lapse data with endpoint measurements such as immunostainings as the hydrogel itself acts as a diffusion barrier. This diffusion barrier impedes supply with fresh nutrients, removal of waste products, and the implementation of efficient washing processes for endpoint staining protocols. In addition, embedding cells into macro 3D matrices complicates cell retrieval after cell cultivation as the hydrogel has to be removed enzymatically or chemically to release embedded cells. [17] In this work, we evaluate a new design of a macro-to-micro interface that can be used for simple and reliable control of microfluidic processes including comprehensive cell culture processes. The presented macro-to-micro interface overcomes significant technical challenges thereby making microfluidic cell culture procedures accessible for biological laboratories.By integrating a workflow that has been described previously, [6] we overcome mentioned limitations and are providing a valuable tool for cultivating single cells, cell-cell pairs, and low cell numbers in spherical hydrogel beads acting as a 3D microenvironment. At the same time, we combine time-lapse (fluorescence) microscopy data with endpoint measurements that provide A new design of a macro-to-micro interface that can be used for simple and reliable control of comprehensive microfluidic cell culture processes is introduced making microfluidic procedures easily accessible to biological laboratories. The novel macro-to-micro interface is evaluated by adapting a workflow for single-cell, cell pair, and cell cluster encapsulation into hydrogel beads acting as 3D microenvironment with subsequent long-term cultivation. For the first time, the coupling of single-cell...

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“…Studies from liver cancer models also showed that anti-VEGR treatment triggered the release of VEGF-enriched exosomes that stimulate angiogenesis (Zeng et al, 2019). EVs can also activate VEGF-independent pathways such as those mediated by hepatocyte growth factor (HGF) to enable TKI-induced cell death (Qu et al, 2016). Exosomal miR-19b derived from cancer stem cells could promote angiogenesis (Wang et al, 2020).…”

Section: Exosomesmentioning

confidence: 99%

“…In human HCC HepG2 cells, Twist1 enhanced the cancer stem-like cell behaviors to adopt an EC-like phenotype, prompting cell motility, invasiveness, and VM formation ( Sun et al, 2010 ). VE-cadherin was transported by extracellular vehicles (EVs) from human umbilical vein endothelial cells (HUVECs) to breast cancer cells, which promotes the VM in a chicken chorioallantois membrane tumor model ( Rezaei et al, 2020 ).…”

Section: Angiogenesis In Tumormentioning

confidence: 99%

Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

Zeng

2020

Front. Cell Dev. Biol.

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Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.

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Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts

Cited by 20 publications

References 55 publications

COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis

COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis

A Macro‐to‐Micro Interface for Performing Comprehensive Microfluidic Cell Culture Assays

Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

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