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13 pages, 2548 KiB

Open AccessArticle

Binding of RNA Aptamers to Membrane Lipid Rafts: Implications for Exosomal miRNAs Transfer from Cancer to Immune Cells

by Teresa Janas, Pawel Janas, Karolina Sapoń and Tadeusz Janas

Int. J. Mol. Sci. 2020, 21(22), 8503; https://doi.org/10.3390/ijms21228503 - 12 Nov 2020

Cited by 21 | Viewed by 2847

Abstract

Intraluminal vesicles (ILVs) are released into the extracellular space as exosomes after the fusion of multivesicular bodies (MVBs) with the plasma membrane. miRNAs are delivered to the raft-like region of MVB by RNA-binding proteins (RBPs). RNA loading into exosomes can be either through [...] Read more.

Intraluminal vesicles (ILVs) are released into the extracellular space as exosomes after the fusion of multivesicular bodies (MVBs) with the plasma membrane. miRNAs are delivered to the raft-like region of MVB by RNA-binding proteins (RBPs). RNA loading into exosomes can be either through direct interaction between RNA and the raft-like region of the MVB membrane, or through interaction between an RBP–RNA complex with this raft-like region. Selection of RNA aptamers that bind to lipid raft region of liposomal membranes was performed using the selection-amplification (SELEX) method. The pool of RNA aptamers was isolated, and the binding of this pool to lipid-raft regions was demonstrated. Sequencing of clones from rafted liposome-eluted RNAs showed sequences apparently of independent origin. Bioinformatics analysis revealed the most frequent raft-motifs present within these sequences. Four raft RNA motifs, one of them an EXO motif, have been identified. These motifs appear to be most frequent both in the case of raft RNA aptamers and in the case of exosomal pro-tumoral miRNAs transferred from cancer cells to macrophages, natural killer cells and dendritic cells, thus suggesting that the selection for incorporation of these miRNAs into ILVs is based on their affinity to the raft-like region of the MVB membrane. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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13 pages, 1624 KiB

Open AccessArticle

The Potential of CD16 on Plasma-Derived Exosomes as a Liquid Biomarker in Head and Neck Cancer

by Linda Hofmann, Sonja Ludwig, Patrick J. Schuler, Thomas K. Hoffmann, Cornelia Brunner and Marie-Nicole Theodoraki

Int. J. Mol. Sci. 2020, 21(11), 3739; https://doi.org/10.3390/ijms21113739 - 26 May 2020

Cited by 21 | Viewed by 3499

Abstract

Head and neck squamous cell carcinomas (HNSCC) are highly immune suppressive and aggressive malignancies. As part of the tumor microenvironment, exosomes contribute to this immune suppression. The Fc receptor CD16 is widely expressed on monocytes, neutrophils, and natural killer (NK) cells and is [...] Read more.

Head and neck squamous cell carcinomas (HNSCC) are highly immune suppressive and aggressive malignancies. As part of the tumor microenvironment, exosomes contribute to this immune suppression. The Fc receptor CD16 is widely expressed on monocytes, neutrophils, and natural killer (NK) cells and is involved in antibody-dependent cell-mediated cytotoxicity (ADCC). Here, surface levels of CD16 on total exosomes and tumor-derived exosomes (TEX) from plasma of HNSCC patients were analyzed regarding their potential as liquid biomarkers for disease stage. Exosomes were isolated from plasma using mini size exclusion chromatography. TEX were enriched by immune affinity capture with CD44v3 antibodies. On-bead flow cytometry was used to measure CD16 levels on total exosomes and TEX. The results were correlated with clinicopathological parameters. Total exosomes from HNSCC patients had significantly higher CD16 levels compared to TEX. Further, CD16 surface levels of total exosomes, but not TEX, correlated with clinicopathological parameters. Patients with advanced tumor stages T3/4 and Union for International Cancer Control (UICC) stages III/IV had significantly higher CD16 levels on total exosomes compared to patients with early tumor stages T1/2 and UICC stages I/II, respectively. Overall, CD16 positive exosomes have the potential as liquid biomarkers for HNSCC tumor stage and aggressiveness. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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18 pages, 14760 KiB

Open AccessArticle

Mass Spectrometry-Based Proteomic Characterization of Cutaneous Melanoma Ectosomes Reveals the Presence of Cancer-Related Molecules

by Magdalena Surman, Sylwia Kędracka-Krok, Dorota Hoja-Łukowicz, Urszula Jankowska, Anna Drożdż, Ewa Ł. Stępień and Małgorzata Przybyło

Int. J. Mol. Sci. 2020, 21(8), 2934; https://doi.org/10.3390/ijms21082934 - 22 Apr 2020

Cited by 16 | Viewed by 3964

Abstract

Cutaneous melanoma (CM) is an aggressive type of skin cancer for which effective biomarkers are still needed. Recently, the protein content of extracellular vesicles (ectosomes and exosomes) became increasingly investigated in terms of its functional role in CM and as a source of [...] Read more.

Cutaneous melanoma (CM) is an aggressive type of skin cancer for which effective biomarkers are still needed. Recently, the protein content of extracellular vesicles (ectosomes and exosomes) became increasingly investigated in terms of its functional role in CM and as a source of novel biomarkers; however, the data concerning the proteome of CM-derived ectosomes is very limited. We used the shotgun nanoLC–MS/MS approach to the profile protein content of ectosomes from primary (WM115, WM793) and metastatic (WM266-4, WM1205Lu) CM cell lines. Additionally, the effect exerted by CM ectosomes on recipient cells was assessed in terms of cell proliferation (Alamar Blue assay) and migratory properties (wound healing assay). All cell lines secreted heterogeneous populations of ectosomes enriched in the common set of proteins. A total of 1507 unique proteins were identified, with many of them involved in cancer cell proliferation, migration, escape from apoptosis, epithelial–mesenchymal transition and angiogenesis. Isolated ectosomes increased proliferation and motility of recipient cells, likely due to the ectosomal transfer of different cancer-promoting molecules. Taken together, these results confirm the significant role of ectosomes in several biological processes leading to CM development and progression, and might be used as a starting point for further studies exploring their diagnostic and prognostic potential. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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Review

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14 pages, 2929 KiB

Open AccessReview

Tumor-Derived Exosomes (TEX) and Their Role in Immuno-Oncology

by Theresa L. Whiteside, Brenda Diergaarde and Chang-Sook Hong

Int. J. Mol. Sci. 2021, 22(12), 6234; https://doi.org/10.3390/ijms22126234 - 9 Jun 2021

Cited by 50 | Viewed by 3745

Abstract

Extracellular vesicles (EVs) play a key role in health and disease, including cancer. Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30–150 nm (virus–size) vesicles originating from [...] Read more.

Extracellular vesicles (EVs) play a key role in health and disease, including cancer. Tumors produce a mix of EVs differing in size, cellular origin, biogenesis and molecular content. Small EVs (sEV) or exosomes are a subset of 30–150 nm (virus–size) vesicles originating from the multivesicular bodies (MVBs) and carrying a cargo that in its content and topography approximates that of a parent cell. Tumor-derived exosomes (TEX) present in all body fluids of cancer patients, are considered promising candidates for a liquid tumor biopsy. TEX also mediate immunoregulatory activities: they maintain a crosstalk between the tumor and various non-malignant cells, including immunocytes. Effects that EVs exert on immune cells may be immunosuppressive or immunostimulatory. Here, we review the available data for TEX interactions with immunocytes, focusing on strategies that allow isolation from plasma and separation of TEX from sEV produced by non-malignant cells. Immune effects mediated by either of the subsets can now be distinguished and measured. The approach has allowed for the comparison of molecular and functional profiles of the two sEV fractions in plasma of cancer patients. While TEX carried an excess of immunosuppressive proteins and inhibited immune cell functions in vitro and in vivo, the sEV derived from non-malignant cells, including CD3(+)T cells, were variably enriched in immunostimulatory proteins and could promote functions of immunocytes. Thus, sEV in plasma of cancer patients are heterogenous, representing a complex molecular network which is not evident in healthy donors’ plasma. Importantly, TEX appear to be able to reprogram functions of non-malignant CD3(+)T cells inducing them to produce CD3(+)sEV enriched in immunosuppressive proteins. Ratios of stimulatory/inhibitory proteins carried by TEX and by CD3(+)sEV derived from reprogrammed non-malignant cells vary broadly in patients and appear to negatively correlate with disease progression. Simultaneous capture from plasma and functional/molecular profiling of TEX and the CD3(+)sEV fractions allows for defining their role as cancer biomarkers and as monitors of cancer patients’ immune competence, respectively. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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17 pages, 1824 KiB

Open AccessReview

CD44 and Tumor-Derived Extracellular Vesicles (TEVs). Possible Gateway to Cancer Metastasis

by Rafał Szatanek and Monika Baj-Krzyworzeka

Int. J. Mol. Sci. 2021, 22(3), 1463; https://doi.org/10.3390/ijms22031463 - 2 Feb 2021

Cited by 26 | Viewed by 6571

Abstract

Cancer metastasis, the final stage of tumor progression, is a complex process governed by the interplay of multiple types of cells and the tumor microenvironment. One of the aspects of this interplay involves the release of various factors by the tumor cells alone [...] Read more.

Cancer metastasis, the final stage of tumor progression, is a complex process governed by the interplay of multiple types of cells and the tumor microenvironment. One of the aspects of this interplay involves the release of various factors by the tumor cells alone or by forcing other cells to do so. As a consequence of these actions, tumor cells are prepared in favorable conditions for their dissemination and spread to other sites/organs, which guarantees their escape from immunosurveillance and further progression. Tumor-derived extracellular vesicles (TEVs) represent a heterogeneous population of membrane-bound vesicles that are being actively released by different tumors. The array of proteins (i.e., receptors, cytokines, chemokines, etc.) and nucleic acids (i.e., mRNA, miR, etc.) that TEVs can transfer to other cells is often considered beneficial for the tumor’s survival and proliferation. One of the proteins that is associated with many different tumors as well as their TEVs is a cluster of differentiation 44 in its standard (CD44s) and variant (CD44v) form. This review covers the present information regarding the TEVs-mediated CD44s/CD44v transfer/interaction in the context of cancer metastasis. The content and the impact of the transferred cargo by this type of TEVs also are discussed with regards to tumor cell dissemination. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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23 pages, 1332 KiB

Open AccessReview

Myeloid Cell Modulation by Tumor-Derived Extracellular Vesicles

by Ihor Arkhypov, Samantha Lasser, Vera Petrova, Rebekka Weber, Christopher Groth, Jochen Utikal, Peter Altevogt and Viktor Umansky

Int. J. Mol. Sci. 2020, 21(17), 6319; https://doi.org/10.3390/ijms21176319 - 31 Aug 2020

Cited by 28 | Viewed by 4823

Abstract

Extracellular vesicles (EV) can carry proteins, RNA and DNA, thus serving as communication tools between cells. Tumor cells secrete EV, which can be taken up by surrounding cells in the tumor microenvironment as well as by cells in distant organs. Tumor-derived EV (TEV) [...] Read more.

Extracellular vesicles (EV) can carry proteins, RNA and DNA, thus serving as communication tools between cells. Tumor cells secrete EV, which can be taken up by surrounding cells in the tumor microenvironment as well as by cells in distant organs. Tumor-derived EV (TEV) contain factors induced by tumor-associated hypoxia such as heat shock proteins or a variety of microRNA (miRNA). The interaction of TEV with tumor and host cells can promote cancer angiogenesis, invasion and metastasis. Myeloid cells are widely presented in tissues, comprise the majority of immune cells and play an essential role in immune reactions and tissue remodeling. However, in cancer, the differentiation of myeloid cells and their functions are impaired, resulting in tumor promotion. Such alterations are due to chronic inflammatory conditions associated with cancer and are mediated by the tumor secretome, including TEV. A high capacity of myeloid cells to clear EV from circulation put them in the central position in EV-mediated formation of pre-metastatic niches. The exposure of myeloid cells to TEV could trigger numerous signaling pathways. Progenitors of myeloid cells alter their differentiation upon the contact with TEV, resulting in the generation of myeloid-derived suppressor cells (MDSC), inhibiting anti-tumor function of T and natural killer (NK) cells and promoting thereby tumor progression. Furthermore, TEV can augment MDSC immunosuppressive capacity. Different subsets of mature myeloid cells such as monocytes, macrophages, dendritic cells (DC) and granulocytes take up TEV and acquire a protumorigenic phenotype. However, the delivery of tumor antigens to DC by TEV was shown to enhance their immunostimulatory capacity. The present review will discuss a diverse and complex EV-mediated crosstalk between tumor and myeloid cells in the context of the tumor type, TEV-associated cargo molecules and type of recipient cells. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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25 pages, 2047 KiB

Open AccessReview

Exosomes in Angiogenesis and Anti-angiogenic Therapy in Cancers

by Wioletta Olejarz, Grażyna Kubiak-Tomaszewska, Alicja Chrzanowska and Tomasz Lorenc

Int. J. Mol. Sci. 2020, 21(16), 5840; https://doi.org/10.3390/ijms21165840 - 14 Aug 2020

Cited by 165 | Viewed by 9905

Abstract

Angiogenesis is the process through which new blood vessels are formed from pre-existing ones. Exosomes are involved in angiogenesis in cancer progression by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. Exosomes promote angiogenesis by suppressing [...] Read more.

Angiogenesis is the process through which new blood vessels are formed from pre-existing ones. Exosomes are involved in angiogenesis in cancer progression by transporting numerous pro-angiogenic biomolecules like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), and microRNAs. Exosomes promote angiogenesis by suppressing expression of factor-inhibiting hypoxia-inducible factor 1 (HIF-1). Uptake of tumor-derived exosomes (TEX) by normal endothelial cells activates angiogenic signaling pathways in endothelial cells and stimulates new vessel formation. TEX-driven cross-talk of mesenchymal stem cells (MSCs) with immune cells blocks their anti-tumor activity. Effective inhibition of tumor angiogenesis may arrest tumor progression. Bevacizumab, a VEGF-specific antibody, was the first antiangiogenic agent to enter the clinic. The most important clinical problem associated with cancer therapy using VEGF- or VEFGR-targeting agents is drug resistance. Combined strategies based on angiogenesis inhibitors and immunotherapy effectively enhances therapies in various cancers, but effective treatment requires further research. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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20 pages, 1195 KiB

Open AccessReview

Perspectives in Manipulating EVs for Therapeutic Applications: Focus on Cancer Treatment

by Katarzyna Nazimek and Krzysztof Bryniarski

Int. J. Mol. Sci. 2020, 21(13), 4623; https://doi.org/10.3390/ijms21134623 - 29 Jun 2020

Cited by 25 | Viewed by 4041

Abstract

Extracellular vesicles (EVs) receive special attention from oncologists due to their assumed usefulness as prognostic markers, vaccines to induce anti-cancer immune response, and physiological delivery tools. The latter application, which supports the reduction of side effects of treatment, is still fraught with many [...] Read more.

Extracellular vesicles (EVs) receive special attention from oncologists due to their assumed usefulness as prognostic markers, vaccines to induce anti-cancer immune response, and physiological delivery tools. The latter application, which supports the reduction of side effects of treatment, is still fraught with many challenges, including established methods for loading EVs with selected cargo and directing them towards target cells. EVs could be loaded with selected cargo either in vitro using several physicochemical techniques, or in vivo by modification of parental cell, which may have an advantage over in vitro procedures, since some of them significantly influence EVs’ properties. Otherwise, our research findings suggest that EVs could be passively supplemented with micro RNAs (miRNAs) or miRNA antagonists to induce expected biological effect. Furthermore, our observations imply that antigen-specific antibody light chains could coat the surface of EVs to increase the specificity of cell targeting. Finally, the route of EVs’ administration also determines their bioavailability and eventually induced therapeutic effect. Besides, EV membrane lipids may possibly possess immune adjuvant activity. The review summarizes the current knowledge on the possibilities to manipulate EVs to use them as a delivery tool, with the special emphasis on anti-cancer therapy. Full article

(This article belongs to the Special Issue EVs in Cross-Talk between Cancer and Immune Cells)

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