The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment

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closed (31 December 2024)

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30 June 2025

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Topic Information

Dear Colleagues,

The tumor microenvironment (TME) is a complex and dynamic ecosystem that influences tumor progression, invasion, metastasis, and treatment response. It is composed of cancer cells, stromal cells, immune cells, and various components of the extracellular matrix and recent research indicates that these components communicate with each other via extracellular vesicles (EVs). EVs are small membrane-bound vesicles released by almost all cells, including cancer cells, and are known to carry various bioactive molecules, such as proteins, nucleic acids, and lipids. This topic is dedicated to the emerging understanding of how EVs contribute to the modulation of the TME. Hereby, we focus on a variety of EV-related aspects, including, but not limited to, EVs as modulators of intercellular communication, the role of EVs in remodeling the extracellular matrix, the immunomodulatory effects of EVs, and EVs as biomarkers and therapeutic targets. We hope that this topic will provide further insights into the complex role of EVs in modulating the TME and will accelerate the development of novel EV-based therapeutic strategies.

Dr. Nils Ludwig
Dr. Miroslaw J Szczepanski
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700	Submit
Current Issues in Molecular Biology cimb	2.8	2.9	1999	15.8 Days	CHF 2200	Submit
Scientia Pharmaceutica scipharm	2.3	4.6	1930	26.1 Days	CHF 1000	Submit
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900	Submit
Current Oncology curroncol	2.8	3.3	1994	19.8 Days	CHF 2200	Submit
Cells cells	5.1	9.9	2012	17 Days	CHF 2700	Submit

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Published Papers (4 papers)

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All Biomolecules CIMB Sci. Pharm. Cancers Current Oncology Cells

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34 pages, 1842 KiB  

Open AccessReview

Cell Progression and Survival Functions of Enzymes Secreted in Extracellular Vesicles Associated with Breast and Prostate Cancers

by Cosmos Ifeanyi Onyiba, Niwasini Krishna Kumar, Christopher J. Scarlett and Judith Weidenhofer

Cells 2025, 14(7), 468; https://doi.org/10.3390/cells14070468 - 21 Mar 2025

Viewed by 1573

Abstract

Extracellular vesicles (EVs) are membrane-bound cargoes secreted by normal and pathological cells. Through their protein, nucleic acid, and lipid cargoes, EVs mediate several cellular processes, such as cell–cell communication, cell development, immune response, and tissue repair. Most importantly, through their enzyme cargo, EVs [...] Read more.

Extracellular vesicles (EVs) are membrane-bound cargoes secreted by normal and pathological cells. Through their protein, nucleic acid, and lipid cargoes, EVs mediate several cellular processes, such as cell–cell communication, cell development, immune response, and tissue repair. Most importantly, through their enzyme cargo, EVs mediate pathophysiological processes, including the pathogenesis of cancer. In this review, we enumerate several enzymes secreted in EVs (EV enzyme cargo) from cells and patient clinical samples of breast and prostate cancers and detail their contributions to the progression and survival of both cancers. Findings in this review reveal that the EV enzyme cargo could exert cell progression functions via adhesion, proliferation, migration, invasion, and metastasis. The EV enzyme cargo might also influence cell survival functions of chemoresistance, radioresistance, angiogenesis, cell death inhibition, cell colony formation, and immune evasion. While the current literature provides evidence of the possible contributions of the EV enzyme cargo to the progression and survival mechanisms of breast and prostate cancers, future studies are required to validate that these effects are modified by EVs and provide insights into the clinical applications of the EV enzyme cargo in breast and prostate cancer. Full article

(This article belongs to the Topic The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment)

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33 pages, 55731 KiB  

Open AccessArticle

Extracellular Signaling Molecules from Adipose-Derived Stem Cells and Ovarian Cancer Cells Induce a Hybrid Epithelial-Mesenchymal Phenotype in a Bidirectional Interaction

by Vinícius Augusto Simão, Juliana Ferreira Floriano, Roberta Carvalho Cesário, Karolina da Silva Tonon, Larissa Ragozo Cardoso de Oliveira, Flávia Karina Delella, Fausto Almeida, Lucilene Delazari dos Santos, Fábio Rodrigues Ferreira Seiva, Débora Aparecida Pires de Campos Zuccari, João Tadeu Ribeiro-Paes, Russel J. Reiter and Luiz Gustavo de Almeida Chuffa

Cells 2025, 14(5), 374; https://doi.org/10.3390/cells14050374 - 4 Mar 2025

Viewed by 2292

Abstract

Ovarian cancer (OC) is characterized by high mortality rates due to late diagnosis, recurrence, and metastasis. Here, we show that extracellular signaling molecules secreted by adipose-derived mesenchymal stem cells (ASCs) and OC cells—either in the conditioned medium (CM) or within small extracellular vesicles [...] Read more.

Ovarian cancer (OC) is characterized by high mortality rates due to late diagnosis, recurrence, and metastasis. Here, we show that extracellular signaling molecules secreted by adipose-derived mesenchymal stem cells (ASCs) and OC cells—either in the conditioned medium (CM) or within small extracellular vesicles (sEVs)—modulate cellular responses and drive OC progression. ASC-derived sEVs and CM secretome promoted OC cell colony formation, invasion, and migration while upregulating tumor-associated signaling pathways, including TGFβ/Smad, p38MAPK/ERK1/2, Wnt/β-catenin, and MMP-9. Additionally, OC-derived sEVs and CM induced a pro-tumorigenic phenotype in ASCs, enhancing their invasiveness and expression of tumor-associated factors. Notably, both ASCs and OC cells exhibited increased expression of E-cadherin and Snail/Slug proteins, key markers of epithelial/mesenchymal hybrid phenotype, enhancing cellular plasticity and metastatic potential. We also demonstrated that these cellular features are, at least in part, due to the presence of tumor-supportive molecules such as TNF-α, Tenascin-C, MMP-2, and SDF-1α in the CM secretome of ASCs and OC cells. In silico analyses linked these molecular changes to poor prognostic outcomes in OC patients. These findings highlight the critical role of sEVs and tumor/stem cell-derived secretome in OC progression through bidirectional interactions that impact cellular behavior and phenotypic transitions. We suggest that targeting EV-mediated communication could improve therapeutic strategies and patient outcomes. Full article

(This article belongs to the Topic The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment)

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12 pages, 1884 KiB  

Open AccessEditor’s ChoiceArticle

Macrophage Phenotype Induced by Circulating Small Extracellular Vesicles from Women with Endometriosis

by María Angeles Martínez-Zamora, Olga Armengol-Badia, Lara Quintas-Marquès, Francisco Carmona and Daniel Closa

Biomolecules 2024, 14(7), 737; https://doi.org/10.3390/biom14070737 - 21 Jun 2024

Cited by 2 | Viewed by 1807

Abstract

Evidence suggests that immune system dysfunction and macrophages are involved in the disease establishment and progression of endometriosis. Among the factors involved in this alteration in macrophage activity, Small Extracellular Vesicles (sEVs) have been described to play a role favoring the switch to [...] Read more.

Evidence suggests that immune system dysfunction and macrophages are involved in the disease establishment and progression of endometriosis. Among the factors involved in this alteration in macrophage activity, Small Extracellular Vesicles (sEVs) have been described to play a role favoring the switch to a specific phenotype with controversial results. This study aims to investigate the potential effect of circulating sEVs in the plasma of well-characterized patients with endometriosis on the polarization of macrophages. sEVs were isolated from the plasma of patients diagnosed with endometriosis confirmed by histopathological analysis. Two groups of patients were recruited: the endometriosis group consisted of patients diagnosed with endometriosis by imaging testing (gynecological ultrasonography and/or magnetic resonance imaging), confirmed by histopathologic study (n = 12), and the control group included patients who underwent laparoscopy for tubal sterilization without presurgical suspicion of endometriosis and without endometriosis or signs of any inflammatory pelvic condition during surgery (n = 12). Human THP1 monocytic cells were differentiated into macrophages, and the effect of sEVs on cell uptake and macrophage polarization was evaluated by fluorescent labeling and measurement of the IL1B, TNF, ARG1, and MRC1 expression, respectively. Although no changes in cell uptake were detected, sEVs from endometriosis induced a polarization of macrophages toward an M2 phenotype, characterized by lower IL1B and TNF expression and a tendency to increase MRC1 and ARG1 levels. When macrophages were stimulated with lipopolysaccharides, less activation was also detected after treatment with endometriosis sEVs. Finally, endometriosis sEVs also induced the expression of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARG); however, treatment with rosiglitazone, a PPARG agonist, had no effect on the change in macrophage phenotype. We conclude that circulating sEVs in women with endometriosis have a certain capacity to shift the activation state of macrophages toward an M2 phenotype, but this does not modify the uptake level or the response to PPARG ligands. Full article

(This article belongs to the Topic The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment)

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13 pages, 4045 KiB  

Open AccessArticle

Biological Activities of Citrus-Derived Extracellular Vesicles on Human Cells: The Role of Preservation

by Theodora Karamanidou, Konstantinos Krommydas, Maria Karanikou, Dimitrios Tsamos, Konstantinos Michalakis, Dimitris Kletsas, Alexander Tsouknidas and Harris Pratsinis

Curr. Issues Mol. Biol. 2024, 46(6), 5812-5824; https://doi.org/10.3390/cimb46060347 - 11 Jun 2024

Cited by 1 | Viewed by 1628

Abstract

Extracellular vesicles (EVs) have been identified as important mediators for cell-to-cell communication. Citrus-based EVs in particular offer an excellent platform for nutraceutical delivery systems, as their endemic cargo includes micronutrients (e.g., ascorbic acid), which contribute to their antioxidant capacity. Despite being extensively investigated [...] Read more.

Extracellular vesicles (EVs) have been identified as important mediators for cell-to-cell communication. Citrus-based EVs in particular offer an excellent platform for nutraceutical delivery systems, as their endemic cargo includes micronutrients (e.g., ascorbic acid), which contribute to their antioxidant capacity. Despite being extensively investigated as to their therapeutic and diagnostic potential, their cargo is inherently unstable and thus directly affected by their storage and preservation. In this study, EVs were isolated from citrus fruit using tangential flow filtration and evaluated for their physicochemical characteristics, antioxidant activity and effects on human cells. To assess how their isolation and preservation methods affect these properties, the EVs were tested immediately after isolation (from fresh and freeze-thawed juices) or following freeze-drying. A measurable biological effect of cryoprotection on citrus-derived EVs was evident, whether during or after isolation. This was more pronounced in the cell-based assays, ranging from −4% to +32% in human skin fibroblast proliferation. Nevertheless, the effects on human cancer cells varied depending on the cell line. Although these results should be considered preliminary observations, subject to further investigation, it is safe to state that any type of preservation is expected to impact the EVs’ biological activity. Full article

(This article belongs to the Topic The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment)

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