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Journal ArticleDOI

Integrin Regulation in Immunological and Cancerous Cells and Exosomes.

23 Feb 2021-International Journal of Molecular Sciences (Multidisciplinary Digital Publishing Institute)-Vol. 22, Iss: 4, pp 2193
TL;DR: In this article, integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology and are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1).
Abstract: Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. It has recently emerged that integrins are expressed not only in cells but also in exosomes, important entities of extracellular vesicles secreted from cells. Exosomal integrins have received considerable attention in recent years, and they are clearly involved in determining the tissue distribution of exosomes, forming premetastatic niches, supporting internalization of exosomes by target cells and mediating exosome-mediated transfer of the membrane proteins and associated kinases to target cells. A growing body of evidence shows that tumor and immune cell exosomes have the ability to alter endothelial characteristics (proliferation, migration) and gene expression, some of these effects being facilitated by vesicle-bound integrins. As endothelial metabolism is now thought to play a key role in tumor angiogenesis, we also discuss how tumor cells and their exosomes pleiotropically modulate endothelial functions in the tumor microenvironment.
Citations
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Journal ArticleDOI
TL;DR: A recent review as discussed by the authors summarizes the progress that has so far been made in the identification of the genomic events that can be used for the classification, prediction and prognostication of prostate cancer, and as major targets for clinical intervention.

32 citations

Journal ArticleDOI
TL;DR: In this article , the most up-to-date information on the clinical relevance of micro-RNAs in bone disorders was brought together to explore their potential as a therapeutic target.
Abstract: MicroRNAs (miRNAs), short, highly conserved non-coding RNA, influence gene expression by sequential mechanisms such as mRNA breakdown or translational repression. Many biological processes depend on these regulating substances, thus changes in their expression have an impact on the maintenance of cellular homeostasis and result in the emergence of a variety of diseases. Relevant studies have shown in recent years that miRNAs are involved in many stages of bone development and growth. Additionally, abnormal production of miRNA in bone tissues has been closely associated with the development of numerous bone disorders, such as osteonecrosis, bone cancer, and bone metastases. Many pathological processes, including bone loss, metastasis, the proliferation of osteosarcoma cells, and differentiation of osteoblasts and osteoclasts, are under the control of miRNAs. By bringing together the most up-to-date information on the clinical relevance of miRNAs in such diseases, this study hopes to further the study of the biological features of miRNAs in bone disorders and explore their potential as a therapeutic target.

17 citations

Journal ArticleDOI
TL;DR: In this article , the functional ligand RGD and magnetic nanoparticles (MNPs) were conjugated onto EV surfaces for pancreatic cancer therapy, which showed a significant reduction in tumor size compared to the free PTX-treated and control groups.

12 citations

Journal ArticleDOI
28 Sep 2021-Cancers
TL;DR: In this article, small extracellular vesicles (sEVs, exosomes) were used as biomarkers for diagnosis and prognosis of pancreatic ductal adenocarcinoma (PDAC).
Abstract: Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30-150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.

9 citations

Journal ArticleDOI
TL;DR: The exosomes in complex interaction mechanisms of angiogenesis and inflammation following stroke as well as the challenges of exosomal studies such as secretion, uptake, modification, and application are discussed.
Abstract: The endothelial dysfunction, associated with inflammation and vascular permeability, remains the key event in the pathogenesis of cerebral ischemic stroke. Angiogenesis is essential for neuroprotection and neural repair following stroke. The neuroinflammatory reaction plays a vital role in stroke, and inhibition of inflammation contributes to establishing an appropriate external environment for angiogenesis. Exosomes are the heterogeneous population of extracellular vesicles which play critical roles in intercellular communication through transmitting various proteins and nucleic acids to nearby and distant recipient cells by body fluids and circulation. Recent reports have shown that exosomal therapy is a valuable and potential treatment strategy for stroke. In this review, we discussed the exosomes in complex interaction mechanisms of angiogenesis and inflammation following stroke as well as the challenges of exosomal studies such as secretion, uptake, modification, and application.

7 citations

References
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Journal ArticleDOI
TL;DR: A comprehensive overview of the current understanding of the physiological roles of EVs is provided, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia.
Abstract: In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

3,690 citations

Journal ArticleDOI
19 Nov 2015-Nature
TL;DR: It is demonstrated that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells.
Abstract: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

3,399 citations

Journal ArticleDOI
TL;DR: It is demonstrated by immunoelectron microscopy that the limiting membrane of MIICs can fuse directly with the plasma membrane, resulting in release from the cells of internal MHC class II-containing vesicles, suggesting a role for exosomes in antigen presentation in vivo.
Abstract: Antigen-presenting cells contain a specialized late endocytic compartment, MIIC (major histocompatibility complex [MHC] class II-enriched compartment), that harbors newly synthesized MHC class II molecules in transit to the plasma membrane. MIICs have a limiting membrane enclosing characteristic internal membrane vesicles. Both the limiting membrane and the internal vesicles contain MHC class II. In this study on B lymphoblastoid cells, we demonstrate by immunoelectron microscopy that the limiting membrane of MIICs can fuse directly with the plasma membrane, resulting in release from the cells of internal MHC class II-containing vesicles. These secreted vesicles, named exosomes, were isolated from the cell culture media by differential centrifugation followed by flotation on sucrose density gradients. The overall surface protein composition of exosomes differed significantly from that of the plasma membrane. Exosome-bound MHC class II was in a compact, peptide-bound conformation. Metabolically labeled MHC class II was released into the extracellular medium with relatively slow kinetics, 10 +/- 4% in 24 h, indicating that direct fusion of MIICs with the plasma membrane is not the major pathway by which MHC class II reaches the plasma membrane. Exosomes derived from both human and murine B lymphocytes induced antigen-specific MHC class II-restricted T cell responses. These data suggest a role for exosomes in antigen presentation in vivo.

2,978 citations

Journal ArticleDOI
TL;DR: This work demonstrates the presence of exosomal and nonexosomal subpopulations within small EVs, and proposes their differential separation by immuno-isolation using either CD63, CD81, or CD9, and provides guidelines to define subtypes of EVs for future functional studies.
Abstract: Extracellular vesicles (EVs) have become the focus of rising interest because of their numerous functions in physiology and pathology. Cells release heterogeneous vesicles of different sizes and intracellular origins, including small EVs formed inside endosomal compartments (i.e., exosomes) and EVs of various sizes budding from the plasma membrane. Specific markers for the analysis and isolation of different EV populations are missing, imposing important limitations to understanding EV functions. Here, EVs from human dendritic cells were first separated by their sedimentation speed, and then either by their behavior upon upward floatation into iodixanol gradients or by immuno-isolation. Extensive quantitative proteomic analysis allowing comparison of the isolated populations showed that several classically used exosome markers, like major histocompatibility complex, flotillin, and heat-shock 70-kDa proteins, are similarly present in all EVs. We identified proteins specifically enriched in small EVs, and define a set of five protein categories displaying different relative abundance in distinct EV populations. We demonstrate the presence of exosomal and nonexosomal subpopulations within small EVs, and propose their differential separation by immuno-isolation using either CD63, CD81, or CD9. Our work thus provides guidelines to define subtypes of EVs for future functional studies.

2,366 citations

Journal ArticleDOI
09 Jul 2015-Nature
TL;DR: GPC1+ crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
Abstract: Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.

2,102 citations