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Extracellular Vesicles and Tumour Microenvironment 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 32982

Special Issue Editor

Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50134 Firenze, Italy
Interests: fibrinolytic system (uPA/uPAR system); tumour invasion and metastasis; angiogenesis; tumour extracellular vesicles; tumour microenvironment; melanoma cells; endothelial cells; cancer immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumour-derived exosomes are emerging mediators of tumorigenesis. Exosomes are small membrane extracellular vesicles (EVs) (40–150 nm) derived from the luminal membranes of multivesicular bodies and are released via fusion with the cell membrane. Exosomes contain bioactive molecules, such as nucleic acids (DNA, mRNA, miRNA, and other noncoding RNAs), proteins (receptors, transcription factors, enzymes, extracellular matrix proteins), and lipids that can redirect the function of a recipient cell. During primary tumour formation, tumour cells require active communication with neighboring cells and their local microenvironment. In recent years, the critical role of EVs in cell–cell communications between tumour cells and surrounding cells in the primary tumour microenvironment has been highlighted. Here, we focus on the role of EVs, and in particular of exosomes, as critical mediators of intracellular communication between tumour cells and stromal cells in local and distant microenvironments.

In particular, the aim of this issue is to elucidate the mode of action of exosomes and their constituents in the context of pre-metastatic niche formation and subsequent metastasis. In fact, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.

Dr. Francesca Margheri
Guest Editor

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Keywords

  • Tumour microenvironment
  • Extracellular vesicles
  • Exosomes
  • Metastasis
  • Interaction between tumour cells and stromal cells
  • Tumour progression

Published Papers (9 papers)

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Research

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10 pages, 1834 KiB  
Article
Pro-Inflammatory Microenvironment Modulates the Transfer of Mutated TP53 Mediated by Tumor Exosomes
by Rossana Domenis, Adriana Cifù, Catia Mio, Martina Fabris and Francesco Curcio
Int. J. Mol. Sci. 2021, 22(12), 6258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126258 - 10 Jun 2021
Cited by 9 | Viewed by 2202
Abstract
Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been [...] Read more.
Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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20 pages, 3948 KiB  
Article
The Interfacial Interactions of Glycine and Short Glycine Peptides in Model Membrane Systems
by Kaitlin A. Doucette, Prangthong Chaiyasit, Donn L. Calkins, Kayli N. Martinez, Cameron Van Cleave, Callan A. Knebel, Anan Tongraar and Debbie C. Crans
Int. J. Mol. Sci. 2021, 22(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010162 - 26 Dec 2020
Cited by 4 | Viewed by 1867
Abstract
The interactions of amino acids and peptides at model membrane interfaces have considerable implications for biological functions, with the ability to act as chemical messengers, hormones, neurotransmitters, and even as antibiotics and anticancer agents. In this study, glycine and the short glycine peptides [...] Read more.
The interactions of amino acids and peptides at model membrane interfaces have considerable implications for biological functions, with the ability to act as chemical messengers, hormones, neurotransmitters, and even as antibiotics and anticancer agents. In this study, glycine and the short glycine peptides diglycine, triglycine, and tetraglycine are studied with regards to their interactions at the model membrane interface of Aerosol-OT (AOT) reverse micelles via 1H NMR spectroscopy, dynamic light scattering (DLS), and Langmuir trough measurements. It was found that with the exception of monomeric glycine, the peptides prefer to associate between the interface and bulk water pool of the reverse micelle. Monomeric glycine, however, resides with the N-terminus in the ordered interstitial water (stern layer) and the C-terminus located in the bulk water pool of the reverse micelle. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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15 pages, 5333 KiB  
Article
mRNA and miRNA Profiles of Exosomes from Cultured Tumor Cells Reveal Biomarkers Specific for HPV16-Positive and HPV16-Negative Head and Neck Cancer
by Sonja Ludwig, Priyanka Sharma, Petra Wise, Richard Sposto, Deborah Hollingshead, Janette Lamb, Stephan Lang, Muller Fabbri and Theresa L. Whiteside
Int. J. Mol. Sci. 2020, 21(22), 8570; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228570 - 13 Nov 2020
Cited by 16 | Viewed by 2461
Abstract
Human papillomavirus (HPV)(+) and HPV(−) head and neck cancer (HNC) cells’ interactions with the host immune system are poorly understood. Recently, we identified molecular and functional differences in exosomes produced by HPV(+) vs. HPV(−) cells, suggesting that genetic cargos of exosomes might identify [...] Read more.
Human papillomavirus (HPV)(+) and HPV(−) head and neck cancer (HNC) cells’ interactions with the host immune system are poorly understood. Recently, we identified molecular and functional differences in exosomes produced by HPV(+) vs. HPV(−) cells, suggesting that genetic cargos of exosomes might identify novel biomarkers in HPV-related HNCs. Exosomes were isolated by size exclusion chromatography from supernatants of three HPV(+) and two HPV(−) HNC cell lines. Paired cell lysates and exosomes were analyzed for messenger RNA (mRNA) by qRT-PCR and microRNA (miR) contents by nanostring analysis. The mRNA profiles of HPV(+) vs. HPV(−) cells were distinct, with EGFR, TP53 and HSPA1A/B overexpressed in HPV(+) cells and IL6, FAS and DPP4 in HPV(−) cells. The mRNA profiles of HPV(+) or HPV(−) exosomes resembled the cargo of their parent cells. miR expression profiles in cell lysates identified 8 miRs expressed in HPV(−) cells vs. 14 miRs in HPV(+) cells. miR-205-5p was exclusively expressed in HPV(+) exosomes, and miR-1972 was only detected in HPV(−) exosomes. We showed that HPV(+) and HPV(−) exosomes recapitulated the mRNA expression profiles of their parent cells. Expression of miRs was dependent on the HPV status, and miR-205-5p in HPV(+) and miR-1972 in HPV(−) exosomes emerge as potential discriminating HPV-associated biomarkers. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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18 pages, 2917 KiB  
Article
Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells
by Shreepa J. Chauhan, Anita Thyagarajan, Yanfang Chen, Jeffrey B. Travers and Ravi P. Sahu
Int. J. Mol. Sci. 2020, 21(22), 8517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228517 - 12 Nov 2020
Cited by 8 | Viewed by 2703
Abstract
Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein [...] Read more.
Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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Review

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13 pages, 9674 KiB  
Review
Time to Classify Tumours of the Stomach and the Kidneys According to Cell of Origin
by Helge Waldum and Patricia Mjønes
Int. J. Mol. Sci. 2021, 22(24), 13386; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413386 - 13 Dec 2021
Cited by 4 | Viewed by 2275
Abstract
Malignant tumours are traditionally classified according to their organ of origin and whether they are of epithelial (carcinomas) or mesenchymal (sarcomas) origin. By histological appearance the site of origin may often be confirmed. Using same treatment for tumours from the same organ is [...] Read more.
Malignant tumours are traditionally classified according to their organ of origin and whether they are of epithelial (carcinomas) or mesenchymal (sarcomas) origin. By histological appearance the site of origin may often be confirmed. Using same treatment for tumours from the same organ is rational only when there is no principal heterogeneity between the tumours of that organ. Organ tumour heterogeneity is typical for the lungs with small cell and non-small cell tumours, for the kidneys where clear cell renal carcinoma (CCRCC) is the dominating type among other subgroups, and in the stomach with adenocarcinomas of intestinal and diffuse types. In addition, a separate type of neuroendocrine tumours (NETs) is found in most organs. Every cell type able to divide may develop into a tumour, and the different subtypes most often reflect different cell origin. In this article the focus is on the cells of origin in tumours arising in the stomach and kidneys and the close relationship between normal neuroendocrine cells and NETs. Furthermore, that the erythropoietin producing cell may be the cell of origin of CCRCC (a cancer with many similarities to NETs), and that gastric carcinomas of diffuse type may originate from the ECL cell, whereas the endodermal stem cell most probably gives rise to cancers of intestinal type. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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22 pages, 12158 KiB  
Review
Next-Generation Biomarkers in Multiple Myeloma: Understanding the Molecular Basis for Potential Use in Diagnosis and Prognosis
by Amro M. Soliman, Srijit Das and Seong Lin Teoh
Int. J. Mol. Sci. 2021, 22(14), 7470; https://doi.org/10.3390/ijms22147470 - 13 Jul 2021
Cited by 14 | Viewed by 5057
Abstract
Multiple myeloma (MM) is considered to be the second most common blood malignancy and it is characterized by abnormal proliferation and an accumulation of malignant plasma cells in the bone marrow. Although the currently utilized markers in the diagnosis and assessment of MM [...] Read more.
Multiple myeloma (MM) is considered to be the second most common blood malignancy and it is characterized by abnormal proliferation and an accumulation of malignant plasma cells in the bone marrow. Although the currently utilized markers in the diagnosis and assessment of MM are showing promising results, the incidence and mortality rate of the disease are still high. Therefore, exploring and developing better diagnostic or prognostic biomarkers have drawn global interest. In the present review, we highlight some of the recently reported and investigated novel biomarkers that have great potentials as diagnostic and/or prognostic tools in MM. These biomarkers include angiogenic markers, miRNAs as well as proteomic and immunological biomarkers. Moreover, we present some of the advanced methodologies that could be utilized in the early and competent diagnosis of MM. The present review also focuses on understanding the molecular concepts and pathways involved in these biomarkers in order to validate and efficiently utilize them. The present review may also help in identifying areas of improvement for better diagnosis and superior outcomes of MM. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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30 pages, 1676 KiB  
Review
Visualizing Extracellular Vesicles and Their Function in 3D Tumor Microenvironment Models
by Evran E. Ural, Victoria Toomajian, Ehsanul Hoque Apu, Mladen Veletic, Ilangko Balasingham, Nureddin Ashammakhi, Masamitsu Kanada and Christopher H. Contag
Int. J. Mol. Sci. 2021, 22(9), 4784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094784 - 30 Apr 2021
Cited by 17 | Viewed by 5427
Abstract
Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. [...] Read more.
Extracellular vesicles (EVs) are cell-derived nanostructures that mediate intercellular communication by delivering complex signals in normal tissues and cancer. The cellular coordination required for tumor development and maintenance is mediated, in part, through EV transport of molecular cargo to resident and distant cells. Most studies on EV-mediated signaling have been performed in two-dimensional (2D) monolayer cell cultures, largely because of their simplicity and high-throughput screening capacity. Three-dimensional (3D) cell cultures can be used to study cell-to-cell and cell-to-matrix interactions, enabling the study of EV-mediated cellular communication. 3D cultures may best model the role of EVs in formation of the tumor microenvironment (TME) and cancer cell-stromal interactions that sustain tumor growth. In this review, we discuss EV biology in 3D culture correlates of the TME. This includes EV communication between cell types of the TME, differences in EV biogenesis and signaling associated with differing scaffold choices and in scaffold-free 3D cultures and cultivation of the premetastatic niche. An understanding of EV biogenesis and signaling within a 3D TME will improve culture correlates of oncogenesis, enable molecular control of the TME and aid development of drug delivery tools based on EV-mediated signaling. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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19 pages, 1075 KiB  
Review
Role of Exosomes in Prostate Cancer Metastasis
by Theresa Akoto and Sharanjot Saini
Int. J. Mol. Sci. 2021, 22(7), 3528; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073528 - 29 Mar 2021
Cited by 51 | Viewed by 7830
Abstract
Prostate cancer remains a life-threatening disease among men worldwide. The majority of PCa-related mortality results from metastatic disease that is characterized by metastasis of prostate tumor cells to various distant organs, such as lung, liver, and bone. Bone metastasis is most common in [...] Read more.
Prostate cancer remains a life-threatening disease among men worldwide. The majority of PCa-related mortality results from metastatic disease that is characterized by metastasis of prostate tumor cells to various distant organs, such as lung, liver, and bone. Bone metastasis is most common in prostate cancer with osteoblastic and osteolytic lesions. The precise mechanisms underlying PCa metastasis are still being delineated. Intercellular communication is a key feature underlying prostate cancer progression and metastasis. There exists local signaling between prostate cancer cells and cells within the primary tumor microenvironment (TME), in addition to long range signaling wherein tumor cells communicate with sites of future metastases to promote the formation of pre-metastatic niches (PMN) to augment the growth of disseminated tumor cells upon metastasis. Over the last decade, exosomes/ extracellular vesicles have been demonstrated to be involved in such signaling. Exosomes are nanosized extracellular vesicles (EVs), between 30 and 150 nm in thickness, that originate and are released from cells after multivesicular bodies (MVB) fuse with the plasma membrane. These vesicles consist of lipid bilayer membrane enclosing a cargo of biomolecules, including proteins, lipids, RNA, and DNA. Exosomes mediate intercellular communication by transferring their cargo to recipient cells to modulate target cellular functions. In this review, we discuss the contribution of exosomes/extracellular vesicles in prostate cancer progression, in pre-metastatic niche establishment, and in organ-specific metastases. In addition, we briefly discuss the clinical significance of exosomes as biomarkers and therapeutic agents. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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10 pages, 637 KiB  
Review
The Influence of a Stressful Microenvironment on Tumor Exosomes: A Focus on the DNA Cargo
by Rossana Domenis, Adriana Cifù and Francesco Curcio
Int. J. Mol. Sci. 2020, 21(22), 8728; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228728 - 19 Nov 2020
Cited by 1 | Viewed by 2038
Abstract
Exosomes secreted by tumor cells, through the transport of bioactive molecules, reprogram the surroundings, building a microenvironment to support the development of the tumor. The discovery that exosomes carry genomic DNA reflecting that of the tumor cell of origin has encouraged studies to [...] Read more.
Exosomes secreted by tumor cells, through the transport of bioactive molecules, reprogram the surroundings, building a microenvironment to support the development of the tumor. The discovery that exosomes carry genomic DNA reflecting that of the tumor cell of origin has encouraged studies to use them as non-invasive biomarkers. The exosome-mediated transfer of oncogenes suggested a new mechanism of malignant transformation that could play a role in the formation of metastases. Several studies have examined the role of tumor exosomes on the modulation of the tumor microenvironment, but relatively few have been directed to assess how stressful stimuli can influence their production and cargo. Understanding the changes in exosome loads and the production pattern of the stressed tumor cell may uncover actionable mechanisms responsible for tumor progression. Full article
(This article belongs to the Special Issue Extracellular Vesicles and Tumour Microenvironment 2.0)
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