scholarly journals Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Huimin Jiang ◽  
Chen Zhou ◽  
Zhen Zhang ◽  
Qiong Wang ◽  
Huimin Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antiangiogenic Therapy ◽  
Cell Phenotype ◽  
Cell Contact ◽  
Perivascular Niche ◽  
Cancer Aggressiveness ◽  
E Box ◽  
Direct Cell

Abstract Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy.

scholarly journals In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

2013 ◽  
Vol 210 (5) ◽  
pp. 951-968 ◽  
Author(s):  
Flavia Pichiorri ◽  
Dario Palmieri ◽  
Luciana De Luca ◽  
Jessica Consiglio ◽  
Jia You ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Human Cancer ◽  
Mirna Regulation ◽  
Altered Expression ◽  
Specific Subset ◽  
Cancer Aggressiveness

Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.

scholarly journals IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation

2008 ◽  
Vol 205 (5) ◽  
pp. 1213-1225 ◽  
Author(s):  
Erwan Mortier ◽  
Tammy Woo ◽  
Rommel Advincula ◽  
Sara Gozalo ◽  
Averil Ma
Keyword(s):  
Nk Cells ◽  
Biosynthetic Pathway ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Contact ◽  
Rapid Responses ◽  
Direct Cell ◽  
Membrane Bound

Natural killer (NK) cells are innate immune effectors that mediate rapid responses to viral antigens. Interleukin (IL)-15 and its high affinity IL-15 receptor, IL-15Rα, support NK cell homeostasis in resting animals via a novel trans presentation mechanism. To better understand how IL-15 and IL-15Rα support NK cell activation during immune responses, we have used sensitive assays for detecting native IL-15 and IL-15Rα proteins and developed an assay for detecting complexes of these proteins. We find that IL-15 and IL-15Rα are preassembled in complexes within the endoplasmic reticulum/Golgi of stimulated dendritic cells (DCs) before being released from cells. IL-15Rα is required for IL-15 production by DCs, and IL-15 that emerges onto the cell surface of matured DCs does not bind to neighboring cells expressing IL-15Rα. We also find that soluble IL-15–IL-15Rα complexes are induced during inflammation, but membrane-bound IL-15–IL-15Rα complexes, rather than soluble complexes, support NK cell activation in vitro and in vivo. Finally, we provide in vivo evidence that expression of IL-15Rα specifically on DCs is critical for trans presenting IL-15 and activating NK cells. These studies define an unprecedented cytokine–receptor biosynthetic pathway in which IL-15Rα serves as a chaperone for IL-15, after which membrane-bound IL-15Rα–IL-15 complexes activate NK cells via direct cell–cell contact.

scholarly journals Activation of contact-dependent antibacterial tRNase toxins by translation elongation factors

2017 ◽  
Vol 114 (10) ◽  
pp. E1951-E1957 ◽  
Author(s):  
Allison M. Jones ◽  
Fernando Garza-Sánchez ◽  
Jaime So ◽  
Christopher S. Hayes ◽  
David A. Low
Keyword(s):  
Coiled Coil ◽  
Elongation Factor ◽  
Nuclease Activity ◽  
Ternary Complexes ◽  
Cell Contact ◽  
Translation Elongation ◽  
Direct Cell ◽  
Dependent Growth

Contact-dependent growth inhibition (CDI) is a mechanism by which bacteria exchange toxins via direct cell-to-cell contact. CDI systems are distributed widely among Gram-negative pathogens and are thought to mediate interstrain competition. Here, we describetsfmutations that alter the coiled-coil domain of elongation factor Ts (EF-Ts) and confer resistance to the CdiA-CTEC869tRNase toxin from enterohemorrhagicEscherichia coliEC869. Although EF-Ts is required for toxicity in vivo, our results indicate that it is dispensable for tRNase activity in vitro. We find that CdiA-CTEC869binds to elongation factor Tu (EF-Tu) with high affinity and this interaction is critical for nuclease activity. Moreover, in vitro tRNase activity is GTP-dependent, suggesting that CdiA-CTEC869only cleaves tRNA in the context of translationally active GTP·EF-Tu·tRNA ternary complexes. We propose that EF-Ts promotes the formation of GTP·EF-Tu·tRNA ternary complexes, thereby accelerating substrate turnover for rapid depletion of target-cell tRNA.

scholarly journals ALK1 as an emerging target for antiangiogenic therapy of cancer

Blood ◽  
2011 ◽  
Vol 117 (26) ◽  
pp. 6999-7006 ◽  
Author(s):  
Sara I. Cunha ◽  
Kristian Pietras
Keyword(s):  
Endothelial Cell ◽  
Antiangiogenic Therapy ◽  
Critical Role ◽  
Tumor Development ◽  
The Body ◽  
Cell Phenotype ◽  
Current View ◽  
Type I

Members of the TGF-β family act on many, if not all, cell types within the body, producing diverse and complex cellular outcomes. Activation of the endothelial cell-restricted TGF-β type I receptor ALK1 results from the binding of several different ligands of the TGF-β family, including bone morphogenetic protein (BMP) 9, BMP10, and TGF-β. Mounting genetic, pharmacologic, and histopathologic evidence supports a critical role for ALK1 signaling in regulation of both developmental and pathologic blood vessel formation. However, the precise function of TGF-β family signaling in endothelial cells is difficult to predict and appears highly context dependent because of the multitude of ligands and receptors influencing the final outcome. Pharmacologic inhibitors of ALK1 have recently been developed and will allow for more accurate studies of ALK1 function in vivo, as well as for assessment of ALK1 as a target for suppression of angiogenesis during tumor development. Herein, we will summarize the current view of ALK1 regulation of endothelial cell phenotype in vitro and in vivo as well as provide an outlook for the ongoing clinical trials of ALK1 inhibitors in malignant disease.

Bovine oocyte maturation: acquisition of developmental competence

2020 ◽  
Vol 32 (2) ◽  
pp. 98
Author(s):  
Bernard A. J. Roelen
Keyword(s):  
Oocyte Maturation ◽  
Developmental Competence ◽  
Cell Contact ◽  
Intimate Contact ◽  
Homologous Chromosomes ◽  
Paracrine Signalling ◽  
Sister Chromatids ◽  
Direct Cell

Although millions of oocytes are formed during embryo and fetal development in the cow, only a small fraction of these will form a developmentally competent oocyte and be fertilised. Development to competence relies on an intimate contact between the oocyte and the surrounding somatic cells in ovarian follicles, via both direct cell–cell contact and paracrine signalling. An important aspect of oocyte maturation is the segregation of homologous chromosomes and subsequently sister chromatids to form a haploid oocyte. Furthermore, the cytoplasm needs to be prepared for the formation of pronuclei and nuclear reprogramming to form a totipotent zygote. Conditions such as high levels of fatty acids or oxidative stress constrain the developmental competence of oocytes, and a better insight into these processes may help improve in vitro and in vivo oocyte maturation success. In addition, identification of the developmentally competent oocyte is useful for the efficiency of (artificial) reproduction.

scholarly journals Requirement of direct contact between chondrocytes and macrophages for the maturation of regenerative cartilage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kengo Kanda ◽  
Yukiyo Asawa ◽  
Ryoko Inaki ◽  
Yuko Fujihara ◽  
Kazuto Hoshi ◽  
...  
Keyword(s):  
Cartilage Regeneration ◽  
Host Cells ◽  
Raw264.7 Cells ◽  
Cell Contact ◽  
Humoral Factors ◽  
Donor Cells ◽  
Direct Cell ◽  
Cell Cell

AbstractRegenerative cartilage prepared from cultured chondrocytes is generally immature in vitro and matures after transplantation. Although many factors, including host cells and humoral factors, have been shown to affect cartilage maturation in vivo, the requirement of direct cell–cell contact between host and donor cells remains to be verified. In this study, we examined the host cells that promote cartilage maturation via cell–cell contact. Based on analysis of the transplanted chondrocytes, we examined the contribution of endothelial cells and macrophages. Using a semiclosed device that is permeable to tissue fluids while blocking host cells, we selectively transplanted chondrocytes and HUVECs or untreated/M1-polarized/M2-polarized RAW264.7 cells. As a result, untreated RAW264.7 cells induced cartilage regeneration. Furthermore, an in vitro coculture assay indicated communication between chondrocytes and RAW264.7 cells mediated by RNA, suggesting the involvement of extracellular vesicles in this process. These findings provide insights for establishing a method of in vitro cartilage regeneration.

scholarly journals Stimulation of metastatic activity of breast cancer cells by plasma exosomes

2016 ◽  
Vol 15 (2) ◽  
pp. 6-15
Author(s):  
R. B. Samsonov ◽  
I. M. Kovalenko ◽  
D. A. Vasilyev ◽  
E. V. Tsyrlina ◽  
G. A. Dashan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Malignant Cell ◽  
Cell Phenotype ◽  
Scattering Method ◽  
Experimental Conditions ◽  
In Vivo Models

Background. Malignant phenotype of cancer cells and metastatic potency of the tumor are determined by genetic factors. In addition, normal biological environment, including the nano-vesicles or exosomes, plays an important role in regulation of the structural and functional characteristics of malignant cells. Objective: presented study was aimed to evaluate mechanisms and to estimate effect of interaction of plasma exosomes and breast cancer cells in experimental conditions. Materials and methods. We used breast cancer cell culture MDA-MB-231 and exosomes isolated from plasma and cultural medium. Exosomes were analyzed by dynamic light scattering method and western blotting. Functional effects of exosomes were evaluated in in vitro and in vivo models. Results. In the present study we demonstrated that plasma exosomes stimulate the adhesion and the motility of breast cancer cells and induce the process of metastatic dissemination. Contact interaction of exosomes with cell surface is sufficient for stimulatory effect that is mediated by exosomal fibronectin and FAK-dependent signaling cascade. Conclusions. Further investigation of plasma exosomes structure and functions is required to better understand their input in regulation of malignant cell phenotype. This research has a potential to provide novel approaches for cancer therapy.

scholarly journals Extracellular vesicles mediate the intercellular exchange of nanoparticles

2021 ◽  
Author(s):  
Xian Wu ◽  
Tang Tang ◽  
Yushuang Wei ◽  
Katherine A. Cummins ◽  
David K. Wood ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Cell Contact ◽  
Therapeutic Effects ◽  
Cellular Receptors ◽  
Transcellular Transport ◽  
Direct Cell ◽  
Intercellular Exchange

AbstractIn order to exert their therapeutic effects, nanoparticles (NPs) often need to travel into the tissues composed of multilayered cells. Accumulative evidence has revealed the central role of transcellular transport route (entry into one cell, exocytosis, and re-entry into another) in this process. While NP endocytosis and subcellular transport have been intensively characterized, the exocytosis and re-entry steps are poorly understood, which becomes a barrier to improve NP delivery into complex tissues. Here, we termed the exocytosis and re-entry steps together as intercellular exchange. We developed a novel collagen-based 3D cellular assay to specifically monitor and quantify the intercellular exchange events of NPs and distinguish the contributions of several potential mechanisms. Our results showed that NPs can be exocytosed freely or enclosed inside extracellular vesicles (EVs) for re-entry, while direct cell-cell contact is hardly involved. EVs account for a significant fraction of NP intercellular exchange, and its importance in NP delivery was demonstrated in vitro and in vivo. Intriguingly, while freely released NPs engage with the same cellular receptors for re-entry, EV-enclosed ones bypass this dependence. These studies provide an easy and precise system to investigate the intercellular exchange stage of NP delivery, and shed the first light in the importance of EVs in NP transport between cells and across complex tissues.

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