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Extracellular Vesicles and the Tumour Microenvironment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 45565

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Special Issue Editor

Prof. Dr. Jameel M. Inal

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Guest Editor

Biosciences Research Group, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK
Interests: extracellular vesicles; cancer; tumour microenvironment; epithelial mesenchymal transition; infectious disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Within the tumour microenvironment, extracellular vesicles (EVs) mediate intercellular communication and the exchange of biomolecules between tumour cells, stromal cells and infiltrating immune cells. These exchanges facilitate tumour expansion through angiogenesis, proliferation, epithelial–mesenchymal transition and ultimately metastasis; tumour EVs also represent an important means by which drug-resistant cancer cells transfer drug efflux pumps. This Special Issue will cover the tumour-protecting immunosuppressive roles of tumour EVs. It will also consider the role tumour EVs play in setting up the pre-metastatic niche and finally question whether inhibition of EV biogenesis or even of particular subtypes could regulate tumour growth and possibly drug resistance.

Prof. Jameel M. Inal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

extracellular vesicles
tumour microenvironment
immunosuppression
premetastatic niche
tumour progression
drug resistance

Published Papers (11 papers)

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Research

Jump to: Review

17 pages, 3033 KiB

Open AccessArticle

Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

by Bibek Bhatta, Ishai Luz, Christian Krueger, Fanny Xueting Teo, David P. Lane, Kanaga Sabapathy and Tomer Cooks

Cancers 2021, 13(12), 2985; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122985 - 15 Jun 2021

Cited by 10 | Viewed by 3094

Abstract

Extracellular vesicles (EVs) shed by cancer cells play a major role in mediating the transfer of molecular information by reprogramming the tumor microenvironment (TME). TP53 (encoding the p53 protein) is the most mutated gene across many cancer types. Mutations in TP53 not only result in the loss of its tumor-suppressive properties but also results in the acquisition of novel gain-of-functions (GOF) that promote the growth of cancer cells. Here, we demonstrate that GOF mutant p53 proteins can be transferred via EVs to neighboring cancer cells and to macrophages, thus modulating them to release tumor supportive cytokines. Our data from pancreatic, lung, and colon carcinoma cell lines demonstrate that the mutant p53 protein can be selectively sorted into EVs. More specifically, mutant p53 proteins in EVs can be taken up by neighboring cells and mutant p53 expression is found in non-tumor cells in both human cancers and in non-human tissues in human xenografts. Our findings shed light on the intricate methods in which specific GOF p53 mutants can promote oncogenic mechanisms by reprogramming and then recruiting non-cancerous elements for tumor progression. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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19 pages, 3470 KiB

Open AccessArticle

Eribulin and Paclitaxel Differentially Alter Extracellular Vesicles and Their Cargo from Triple-Negative Breast Cancer Cells

by Petra J. Pederson, Huiyun Liang, Daria Filonov and Susan L. Mooberry

Cancers 2021, 13(11), 2783; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13112783 - 03 Jun 2021

Cited by 8 | Viewed by 2915

Abstract

Extracellular vesicles play a central role in intercellular communication and contribute to cancer progression, including the epithelial-to-mesenchymal transition (EMT). Microtubule targeting agents (MTAs) including eribulin and paclitaxel continue to provide significant value in cancer therapy and their abilities to inhibit oncogenic signaling pathways, including eribulin’s capacity to reverse EMT are being revealed. Because microtubules are involved in the intracellular trafficking required for the formation and cargo loading of small extracellular vesicles (sEVs), we investigated whether MTA-mediated disruption of microtubule-dependent transport would impact sEV release and their cargo. Eribulin and paclitaxel caused an intracellular accumulation of CD63, a tetraspanin component of sEVs, in late/multivesicular endosomes of triple-negative breast cancer cells, consistent with the disruption of endosomal sorting and exosome cargo loading in these cells. While the concentrations of sEVs released from MTA-treated cells were not significantly altered, levels of CD63 and the CD63-associated cargos, ILK and β-integrin, were reduced in sEVs isolated from eribulin-treated HCC1937 cells as compared to vehicle or paclitaxel-treated cells. These results show that eribulin can reduce specific sEV cargos, including ILK, a major transducer of EMT in the tumor microenvironment, which may contribute to eribulin’s ability to reverse EMT to promote anticancer efficacy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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21 pages, 3220 KiB

Open AccessArticle

Distinct mRNAs in Cancer Extracellular Vesicles Activate Angiogenesis and Alter Transcriptome of Vascular Endothelial Cells

by Pan Zhang, Su Bin Lim, Kuan Jiang, Ti Weng Chew, Boon Chuan Low and Chwee Teck Lim

Cancers 2021, 13(9), 2009; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092009 - 22 Apr 2021

Cited by 5 | Viewed by 2599

Abstract

Cancer-derived extracellular vesicles (EVs) have been demonstrated to be implicated in various processes of cancer development, with most of the EV-induced changes attributed to EV-proteins and EV-microRNAs. However, the knowledge about the abundance of cancer EV-mRNAs and their contribution to cancer development remain elusive. Here, we show that mRNAs prevail in cancer EVs as compared with normal EVs, and cancer EVs that carry abundant angiogenic mRNAs activate angiogenesis in human umbilical vein endothelial cells (HUVECs). Specifically, of a gene panel comprising 61 hypoxia-targeted oncogenes, a larger proportion is harbored by cancer EVs (>40%) than normal EVs (14.8%). Fluorescent trafficking indicates cancer EVs deliver translatable mRNAs such as VEGFA to HUVECs, contributing to the activation of VEGFR-dependent angiogenesis and the upregulation of epithelial-mesenchymal transition-related and metabolism-related genes. Overall, our findings provide novel insights into EV-mRNAs and their role in angiogenesis, and has potential for diagnostic and therapeutic applications. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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19 pages, 4358 KiB

Open AccessArticle

Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

by Alekhya Mazumdar, Joaquin Urdinez, Aleksandar Boro, Matthias J. E. Arlt, Fabian E. Egli, Barbara Niederöst, Patrick K. Jaeger, Greta Moschini, Roman Muff, Bruno Fuchs, Jess G. Snedeker and Ana Gvozdenovic

Cancers 2020, 12(11), 3457; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12113457 - 20 Nov 2020

Cited by 21 | Viewed by 3464

Abstract

The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b⁺ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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28 pages, 4353 KiB

Open AccessArticle

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

by Yuka Okusha, Takanori Eguchi, Manh T. Tran, Chiharu Sogawa, Kaya Yoshida, Mami Itagaki, Eman A. Taha, Kisho Ono, Eriko Aoyama, Hirohiko Okamura, Ken-ichi Kozaki, Stuart K. Calderwood, Masaharu Takigawa and Kuniaki Okamoto

Cancers 2020, 12(4), 881; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040881 - 04 Apr 2020

Cited by 36 | Viewed by 5093

Abstract

Matrix metalloproteinase 3 (MMP3) plays multiple roles in extracellular proteolysis as well as intracellular transcription, prompting a new definition of moonlighting metalloproteinase (MMP), according to a definition of protein moonlighting (or gene sharing), a phenomenon by which a protein can perform more than one function. Indeed, connective tissue growth factor (CTGF, aka cellular communication network factor 2 (CCN2)) is transcriptionally induced as well as cleaved by MMP3. Moreover, several members of the MMP family have been found within tumor-derived extracellular vesicles (EVs). We here investigated the roles of MMP3-rich EVs in tumor progression, molecular transmission, and gene regulation. EVs derived from a rapidly metastatic cancer cell line (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich, LuM1-derived EVs were disseminated to multiple organs through body fluid and were pro-tumorigenic in an allograft mouse model, which prompted us to define LuM1-EVs as oncosomes in the present study. Oncosome-derived MMP3 was transferred into recipient cell nuclei and thereby trans-activated the CCN2/CTGF promoter, and induced CCN2/CTGF production in vitro. TRENDIC and other cis-elements in the CCN2/CTGF promoter were essential for the oncosomal responsivity. The CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects such as the inhibition of migration and invasion of tumor cells, and a reduction in CCN2/CTGF promoter activity and fragmentations in vitro. A high expression level of MMP3 or CCN2/CTGF mRNA was prognostic and unfavorable in particular types of cancers including head and neck, lung, pancreatic, cervical, stomach, and urothelial cancers. These data newly demonstrate that oncogenic EVs-derived MMP is a transmissive trans-activator for the cellular communication network gene and promotes tumorigenesis at distant sites. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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Review

Jump to: Research

17 pages, 850 KiB

Open AccessReview

Extracellular Vesicles in Advanced Prostate Cancer: Tools to Predict and Thwart Therapeutic Resistance

by Carolina Saldana, Amene Majidipur, Emma Beaumont, Eric Huet, Alexandre de la Taille, Francis Vacherot, Virginie Firlej and Damien Destouches

Cancers 2021, 13(15), 3791; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153791 - 28 Jul 2021

Cited by 5 | Viewed by 3014

Abstract

Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. At first, advanced PCa is treated by androgen deprivation therapy with a good initial response. Nevertheless, recurrences occur, leading to Castrate-Resistance Prostate Cancer (CRPC). During the last decade, new therapies based on inhibition of the androgen receptor pathway or taxane chemotherapies have been used to treat CRPC patients leading to an increase in overall survival, but the occurrence of resistances limits their benefits. Numerous studies have demonstrated the implication of extracellular vesicles (EVs) in different cancer cellular mechanisms. Thus, the possibility to isolate and explore EVs produced by tumor cells in plasma/sera represents an important opportunity for the deciphering of those mechanisms and the discovery of biomarkers. Herein, we summarized the role of EVs in therapeutic resistance of advanced prostate cancer and their use to find biomarkers able to predict these resistances. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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23 pages, 1553 KiB

Open AccessEditor’s ChoiceReview

Adipose Tissue-Derived Extracellular Vesicles and the Tumor Microenvironment: Revisiting the Hallmarks of Cancer

by João Alfredo Moraes, Carol Encarnação, Victor Aguiar Franco, Luiz Gabriel Xavier Botelho, Gabriella Pacheco Rodrigues, Isadora Ramos-Andrade, Christina Barja-Fidalgo and Mariana Renovato-Martins

Cancers 2021, 13(13), 3328; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133328 - 02 Jul 2021

Cited by 23 | Viewed by 4314

Abstract

Extracellular vesicles (EVs) are crucial elements that sustain the communication between tumor cells and their microenvironment, and have emerged as a widespread mechanism of tumor formation and metastasis. In obesity, the adipose tissue becomes hypertrophic and hyperplastic, triggering increased production of pro-inflammatory adipokines, such as tumor necrosis factor α, interleukin 6, interleukin 1, and leptin. Furthermore, obese adipose tissue undergoes dysregulation in the cargo content of the released EVs, resulting in an increased content of pro-inflammatory proteins, fatty acids, and oncogenic microRNAs. These alterations drive obesity-associated inflammatory responses both locally and systemically. After being ignored for a long time, adipose tissues have recently received considerable attention as a major player in tumor microenvironment-linked obesity and cancer. The role of adipose tissue in the establishment and progression of cancer is reinforced by its high plasticity and inflammatory content. Such a relationship may be established by direct contact between adipocytes and cancer cells within the microenvironment or systemically, via EV-mediated cell-to-cell communication. Here, we highlight cues evidencing the influence of adipose tissue-derived EVs on the hallmarks of cancer, which are critical for tumor malignancy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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22 pages, 15049 KiB

Open AccessReview

Regulation of Antitumor Immune Responses by Exosomes Derived from Tumor and Immune Cells

by Andrés Rincón-Riveros, Liliana Lopez, E Victoria Villegas and Josefa Antonia Rodriguez

Cancers 2021, 13(4), 847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040847 - 17 Feb 2021

Cited by 14 | Viewed by 3290

Abstract

Exosomes are lipid membrane-enclosed vesicles released by all cell types that act at the paracrine or endocrine level to favor cell differentiation, tissue homeostasis, organ remodeling and immune regulation. Their biosynthesis begins with a cell membrane invagination which generates an early endosome that matures to a late endosome. By inward budding of the late endosome membrane, a multivesicular body (MVB) with intraluminal vesicles (ILVs) is generated. The fusion of MVBs with the plasma membrane releases ILVs into the extracellular space as exosomes, ranging in size from 30 to 100 nm in diameter. The bilipid exosome membrane is rich in cholesterol, ceramides and phosphatidylserine and can be loaded with DNA, RNA, microRNAs, proteins and lipids. It has been demonstrated that exosome secretion is a common mechanism used by the tumor to generate an immunosuppressive microenvironment that favors cancer development and progression, allowing tumor escape from immune control. Due to their ability to transport proteins, lipids and nucleic acids from the cell that gave rise to them, exosomes can be used as a source of biomarkers with great potential for clinical applications in diagnostic, prognostic or therapeutic areas. This article will review the latest research findings on exosomes and their contribution to cancer development. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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Graphical abstract

16 pages, 1154 KiB

Open AccessReview

Emerging Role of Extracellular Vesicles in Immune Regulation and Cancer Progression

by Sonam Mittal, Prachi Gupta, Pradeep Chaluvally-Raghavan and Sunila Pradeep

Cancers 2020, 12(12), 3563; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123563 - 28 Nov 2020

Cited by 42 | Viewed by 5193

Abstract

The development of effective therapies for cancer treatment requires a better understanding of the tumor extracellular environment and a dynamic interaction between tumor cells, the cells of the immune system, and the tumor stroma. Increasing evidence suggests that extracellular vesicles play an important role in this interaction. Extracellular vesicles are nanometer-sized membrane-bound vesicles secreted by various types of cells that facilitate intracellular communication by transferring proteins, various lipids, and nucleic acids, especially miRNAs, between cells. Extracellular vesicles play discrete roles in the immune regulatory functions, such as antigen presentation, and activation or suppression of immune cells. Achieving therapeutic intervention through targeting of extracellular vesicles is a crucial area of research now. Thus, a deeper knowledge of exosome biology and the molecular mechanism of immune regulation is likely to provide significant insight into therapeutic intervention utilizing extracellular vesicles to combat this dreadful disease. This review describes the recent updates on immune regulation by extracellular vesicles in cancer progression and possible use in cancer therapy. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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21 pages, 1192 KiB

Open AccessReview

Extracellular Vesicles as Biomarkers in Cancer Immunotherapy

by Matthen Mathew, Mariam Zade, Nadia Mezghani, Romil Patel, Yu Wang and Fatemeh Momen-Heravi

Cancers 2020, 12(10), 2825; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102825 - 30 Sep 2020

Cited by 64 | Viewed by 6116

Abstract

Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound vesicles secreted by most cell types during both physiologic conditions as well in response to cellular stress. EVs play an important role in intercellular communication and are emerging as key players in tumor immunology. Tumor-derived EVs (TDEs) harbor a diverse array of tumor neoantigens and contain unique molecular signature that is reflective of tumor’s underlying genetic complexity. As such they offer a glimpse into the immune tumor microenvironment (TME) and have the potential to be a novel, minimally invasive biomarker for cancer immunotherapy. Immune checkpoint inhibitors (ICI), such as anti- programmed death-1(PD-1) and its ligand (PD-L1) antibodies, have revolutionized the treatment of a wide variety of solid tumors including head and neck squamous cell carcinoma, urothelial carcinoma, melanoma, non-small cell lung cancer, and others. Typically, an invasive tissue biopsy is required both for histologic diagnosis and next-generation sequencing efforts; the latter have become more widespread in daily clinical practice. There is an unmet need for noninvasive or minimally invasive (e.g., plasma-based) biomarkers both for diagnosis and treatment monitoring. Targeted analysis of EVs in biospecimens, such as plasma and saliva could serve this purpose by potentially obviating the need for tissue sample. In this review, we describe the current challenges of biomarkers in cancer immunotherapy as well as the mechanistic role of TDEs in modulating antitumor immune response. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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22 pages, 716 KiB

Open AccessReview

Exosomal MicroRNAs and Organotropism in Breast Cancer Metastasis

by Grace L. Wong, Sara Abu Jalboush and Hui-Wen Lo

Cancers 2020, 12(7), 1827; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071827 - 07 Jul 2020

Cited by 38 | Viewed by 4986

Abstract

Breast cancer is the most frequent malignancy for women in which one in eight women will be diagnosed with the disease in their lifetime. Despite advances made in treating primary breast cancer, there is still no effective treatment for metastatic breast cancer. Consequently, metastatic breast cancer is responsible for 90% of breast cancer-related deaths while only accounting for approximately one third of all breast cancer cases. To help develop effective treatments for metastatic breast cancer, it is important to gain a deeper understanding of the mechanisms by which breast cancer metastasizes, particularly, those underlying organotropism towards brain, bone, and lungs. In this review, we will primarily focus on the roles that circulating exosomal microRNAs (miRNAs) play in organotropism of breast cancer metastasis. Exosomes are extracellular vesicles that play critical roles in intercellular communication. MicroRNAs can be encapsulated in exosomes; cargo-loaded exosomes can be secreted by tumor cells into the tumor microenvironment to facilitate tumor–stroma interactions or released to circulation to prime distant organs for subsequent metastasis. Here, we will summarize our current knowledge on the biogenesis of exosomes and miRNAs, mechanisms of cargo sorting into exosomes, the exosomal miRNAs implicated in breast cancer metastasis, and therapeutic exosomal miRNAs. Full article

(This article belongs to the Special Issue Extracellular Vesicles and the Tumour Microenvironment)

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