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Biomarker Research May 2022Exosomes, ranging in size from 30 to 150 nm as identified initially via electron microscopy in 1946, are one of the extracellular vesicles (EVs) produced by many cells... (Review)
Review
Exosomes, ranging in size from 30 to 150 nm as identified initially via electron microscopy in 1946, are one of the extracellular vesicles (EVs) produced by many cells and have been the subject of many studies; initially, they were considered as cell wastes with the belief that cells produced exosomes to maintain homeostasis. Nowadays, it has been found that EVs secreted by different cells play a vital role in cellular communication and are usually secreted in both physiological and pathological conditions. Due to the presence of different markers and ligands on the surface of exosomes, they have paracrine, endocrine and autocrine effects in some cases. Immune cells, like other cells, can secrete exosomes that interact with surrounding cells via these vesicles. Immune system cells-derived exosomes (IEXs) induce different responses, such as increasing and decreasing the transcription of various genes and regulating cytokine production. This review deliberate the function of innate and acquired immune cells derived exosomes, their role in the pathogenesis of immune diseases, and their therapeutic appliances.
PubMed: 35550636
DOI: 10.1186/s40364-022-00374-4 -
Biochemistry and Biophysics Reports Jul 2022Autocrine and paracrine signals are of paramount importance in both normal and oncogenic events and the composition of such secreted molecular signals (i.e the...
Autocrine and paracrine signals are of paramount importance in both normal and oncogenic events and the composition of such secreted molecular signals (i.e the secretome) designate the communication status of cells. In this context, the analysis of post-translational modifications in secreted proteins may unravel biological circuits regulated by irreversible modifications such as proteolytic processing. In the present study, we have performed a bioinformatic reanalysis of public proteomics data on melanoma cell line secretomes, changing database searching parameters to allow for the identification of proteolytic events generated by active proteases. Such approach enabled the identification of proteolytic signatures which suggested active proteases and whose expression profiles might be targeted in patient tissues or liquid biopsies, as well as their cleaved substrates. Although N-terminomics approaches continue to be the method of choice for the evaluation of proteolytic signaling events in complex samples, the simple approach performed in this work resulted in the gain of biological insights derived from shotgun proteomics data.
PubMed: 35462751
DOI: 10.1016/j.bbrep.2022.101259 -
Oncogene May 2022Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have...
Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.
Topics: Autocrine Communication; Chemokines; Glioblastoma; Humans; NF-kappa B; Paracrine Communication; Receptors, Chemokine; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 35459783
DOI: 10.1038/s41388-022-02295-w -
Biomedicines Mar 2022Bone tissue remodeling is a highly regulated process balancing bone formation and resorption through complex cellular crosstalk between resident bone and... (Review)
Review
Bone tissue remodeling is a highly regulated process balancing bone formation and resorption through complex cellular crosstalk between resident bone and microenvironment cells. This cellular communication is mediated by direct cell and cell-matrix contact, autocrine, endocrine, and paracrine receptor mediated mechanisms such as local soluble signaling molecules and extracellular vesicles including nanometer sized exosomes. An impairment in this balanced process leads to development of pathological conditions. Bone tissue engineering is an emerging interdisciplinary field with potential to address bone defects and disorders by synthesizing three-dimensional bone substitutes embedded with cells for clinical implantation. However, current cell-based therapeutic approaches have faced hurdles due to safety and ethical concerns, challenging their clinical translation. Recent studies on exosome-regulated bone homeostasis and regeneration have gained interest as prospective cell free therapy in conjugation with tissue engineered bone grafts. However, exosome research is still in its nascent stages of bone tissue engineering. In this review, we specifically describe the role of exosomes secreted by cells within bone microenvironment such as osteoblasts, osteocytes, osteoclasts, mesenchymal stem cell cells, immune cells, endothelial cells, and even tumor cells during bone homeostasis and crosstalk. We also review exosome-based osteoinductive functionalization strategies for various bone-based biomaterials such as ceramics, polymers, and metals in bone tissue engineering. We further highlight biomaterials as carrier agents for exosome delivery to bone defect sites and, finally, the influence of various biomaterials in modulation of cell exosome secretome.
PubMed: 35453517
DOI: 10.3390/biomedicines10040767 -
Frontiers in Immunology 2022Exosomes are small extracellular vesicles that are secreted by almost all types of cells and exist in almost all extracellular spaces. As an important mediator of... (Review)
Review
Exosomes are small extracellular vesicles that are secreted by almost all types of cells and exist in almost all extracellular spaces. As an important mediator of intercellular communication, exosomes encapsulate the miRNA, lncRNA, cirRNA, mRNA, cytokine, enzyme, lipid, and other components from the cytoplasm into its closed single membrane structure and transfer them to recipient units in an autocrine, paracrine, or endocrine manner. Hypoxia is a state of low oxygen tension and is involved in many pathological processes. Hypoxia influences the size, quantity, and expression of exosome cargos. Exosomes derived from hypoxic tumor cells transfer genetics, proteins, and lipids to the recipient units to exert pleiotropic effects. Different donor cells produce different cargo contents, target different recipient units and lead to different biological effects. Hypoxic exosomes derived from tumor cells uptaken by normoxic tumor cells lead to promoted proliferation, migration, and invasion; uptaken by extracellular space or liver lead to promoted metastasis; uptaken by endothelial cells lead to promoted angiogenesis; uptaken by immune cells lead to promoted macrophage polarization and changed tumor immune microenvironment. In addition to various types of tumors, hypoxic exosomes also participate in the development of diseases in the cardiovascular system, neuron system, respiratory system, hematology system, endocrine system, urinary system, reproduction system, and skeletomuscular system. Understanding the special characteristics of hypoxic exosomes provide new insight into elaborating the pathogenesis of hypoxia related disease. This review summarizes hypoxia induced cargo changes and the biological effects of hypoxic exosomes in tumors and non-malignant diseases in different systems.
Topics: Cell Communication; Endothelial Cells; Exosomes; Humans; Hypoxia; Neoplasms; Tumor Microenvironment
PubMed: 35444652
DOI: 10.3389/fimmu.2022.824188 -
Journal of Cancer 2022Hypoxia is a key feature of solid tumors and is related to disease aggressiveness and adverse outcomes. It is recognized that the two-way communication between cancer... (Review)
Review
Hypoxia is a key feature of solid tumors and is related to disease aggressiveness and adverse outcomes. It is recognized that the two-way communication between cancer cells and their microenvironment is critical to cancer progression. Increasing evidences show that the cellular communication and crosstalk between tumor cells and their microenvironment is not limited to secreted molecules, but also includes exosomes secreted by tumor cells. Exosomes are nano-scale extracellular vesicles (30-100 nm in diameter), which carry the molecular characteristics and cargo of the source cell, participating in intercellular communication through autocrine, paracrine and near-crine pathways. Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than normoxia conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Therefore, in this review, we summarize and discuss the latest research on the physiological mechanism of hypoxia regulating the secretion of exosomes, and the involvement of hypoxic exosomes in cancer progression and immune escape processes, and expounds the potential for targeting hypoxia-induced exosomes for cancer therapy strategies.
PubMed: 35371323
DOI: 10.7150/jca.69278 -
Cell & Bioscience Mar 2022Extracellular vesicle (EV) secretion is a highly conserved evolutionary trait in all organisms in the three domains of life. The packaging and release of EVs appears to... (Review)
Review
Extracellular vesicle (EV) secretion is a highly conserved evolutionary trait in all organisms in the three domains of life. The packaging and release of EVs appears to be a bulk-flow process which takes place mainly under extreme conditions. EVs participate in horizontal gene transfer, which supports the survival of prokaryotic and eukaryotic microbes. In higher eukaryotes, almost all cells secrete a heterogeneous population of EVs loaded with various biomolecules. EV secretion is typically higher in cancer microenvironments, promoting tumor progression and metastasis. EVs are now recognized as additional mediators of autocrine and paracrine communication in health and disease. In this context, proteins and RNAs have been studied the most, but extracellular vesicle DNA (EV-DNA) has started to gain in importance in the last few years. In this review, we summarize new findings related to the loading mechanism(s), localization, and post-shedding function of EV-DNA. We also discuss the feasibility of using EV-DNA as a biomarker when performing a liquid biopsy, at the same time emphasizing the lack of data from clinical trials in this regard. Finally, we outline the potential of EV-DNA uptake and its interaction with the host genome as a promising tool for understanding the mechanisms of cancer evolution.
PubMed: 35346363
DOI: 10.1186/s13578-022-00771-0 -
G3 (Bethesda, Md.) May 2022Animal development requires coordinated communication between cells. The Connexin family of proteins is a major contributor to intercellular communication in vertebrates...
Animal development requires coordinated communication between cells. The Connexin family of proteins is a major contributor to intercellular communication in vertebrates by forming gap junction channels that facilitate the movement of ions, small molecules, and metabolites between cells. Additionally, individual hemichannels can provide a conduit to the extracellular space for paracrine and autocrine signaling. Connexin-mediated communication is widely used in epithelial, neural, and vascular development and homeostasis, and most tissues likely use this form of communication. In fact, Connexin disruptions are of major clinical significance contributing to disorders developing from all major germ layers. Despite the fact that Connexins serve as an essential mode of cellular communication, the temporal and cell-type-specific expression patterns of connexin genes remain unknown in vertebrates. A major challenge is the large and complex connexin gene family. To overcome this barrier, we determined the expression of all connexins in zebrafish using single-cell RNA-sequencing of entire animals across several stages of organogenesis. Our analysis of expression patterns has revealed that few connexins are broadly expressed, but rather, most are expressed in tissue- or cell-type-specific patterns. Additionally, most tissues possess a unique combinatorial signature of connexin expression with dynamic temporal changes across the organism, tissue, and cell. Our analysis has identified new patterns for well-known connexins and assigned spatial and temporal expression to genes with no-existing information. We provide a field guide relating zebrafish and human connexin genes as a critical step toward understanding how Connexins contribute to cellular communication and development throughout vertebrate organogenesis.
Topics: Animals; Cell Communication; Connexins; Gap Junctions; Organogenesis; Zebrafish
PubMed: 35325106
DOI: 10.1093/g3journal/jkac062 -
PLoS Computational Biology Mar 2022In many human cancers, the rate of cell growth depends crucially on the size of the tumor cell population. Low, zero, or negative growth at low population densities is...
In many human cancers, the rate of cell growth depends crucially on the size of the tumor cell population. Low, zero, or negative growth at low population densities is known as the Allee effect; this effect has been studied extensively in ecology, but so far lacks a good explanation in the cancer setting. Here, we formulate and analyze an individual-based model of cancer, in which cell division rates are increased by the local concentration of an autocrine growth factor produced by the cancer cells themselves. We show, analytically and by simulation, that autocrine signaling suffices to cause both strong and weak Allee effects. Whether low cell densities lead to negative (strong effect) or reduced (weak effect) growth rate depends directly on the ratio of cell death to proliferation, and indirectly on cellular dispersal. Our model is consistent with experimental observations from three patient-derived brain tumor cell lines grown at different densities. We propose that further studying and quantifying population-wide feedback, impacting cell growth, will be central for advancing our understanding of cancer dynamics and treatment, potentially exploiting Allee effects for therapy.
Topics: Autocrine Communication; Ecology; Feedback; Humans; Models, Biological; Neoplasms; Population Density; Population Dynamics
PubMed: 35239640
DOI: 10.1371/journal.pcbi.1009844 -
Cell Communication and Signaling : CCS Feb 2022Signaling pathways allow cells to detect and respond to a wide variety of chemical (e.g. Ca or chemokine proteins) and physical stimuli (e.g., sheer stress, light).... (Review)
Review
Signaling pathways allow cells to detect and respond to a wide variety of chemical (e.g. Ca or chemokine proteins) and physical stimuli (e.g., sheer stress, light). Together, these pathways form an extensive communication network that regulates basic cell activities and coordinates the function of multiple cells or tissues. The process of cell signaling imposes many demands on the proteins that comprise these pathways, including the abilities to form active and inactive states, and to engage in multiple protein interactions. Furthermore, successful signaling often requires amplifying the signal, regulating or tuning the response to the signal, combining information sourced from multiple pathways, all while ensuring fidelity of the process. This sensitivity, adaptability, and tunability are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling. The goal of this collection is to highlight the many roles of intrinsic disorder in cell signaling. Following an overview of resources that can be used to study intrinsically disordered proteins, this review highlights the critical role of intrinsically disordered proteins for signaling in widely diverse organisms (animals, plants, bacteria, fungi), in every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine) and at each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process. Thus, a cell signaling pathway cannot be fully described without understanding how intrinsically disordered protein regions contribute to its function. The ubiquitous presence of intrinsic disorder in different stages of diverse cell signaling pathways suggest that more mechanisms by which disorder modulates intra- and inter-cell signals remain to be discovered.
Topics: Animals; Cell Communication; Intrinsically Disordered Proteins; Signal Transduction
PubMed: 35177069
DOI: 10.1186/s12964-022-00821-7