Exploiting Manipulated Small Extracellular Vesicles to Subvert Immunosuppression at the Tumor Microenvironment through Mannose Receptor/CD206 Targeting

Immunosuppression at tumor microenvironment (TME) is one of the major obstacles to be overcome for an effective therapeutic intervention against solid tumors. Tumor-associated macrophages (TAMs) comprise a sub-population that plays multiple pro-tumoral roles in tumor development including general immunosuppression, which can be identified in terms of high expression of mannose receptor (MR or CD206). Immunosuppressive TAMs, like other macrophage sub-populations, display functional plasticity that allows them to be re-programmed to inflammatory macrophages. In order to mitigate immunosuppression at the TME, several efforts are ongoing to effectively re-educate pro-tumoral TAMs. Extracellular vesicles (EVs), released by both normal and tumor cells types, are emerging as key mediators of the cell to cell communication and have been shown to have a role in the modulation of immune responses in the TME. Recent studies demonstrated the enrichment of high mannose glycans on the surface of small EVs (sEVs), a subtype of EVs of endosomal origin of 30–150 nm in diameter. This characteristic renders sEVs an ideal tool for the delivery of therapeutic molecules into MR/CD206-expressing TAMs. In this review, we report the most recent literature data highlighting the critical role of TAMs in tumor development, as well as the experimental evidences that has emerged from the biochemical characterization of sEV membranes. In addition, we propose an original way to target immunosuppressive TAMs at the TME by endogenously engineered sEVs for a new therapeutic approach against solid tumors.

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On the Choice of the Extracellular Vesicles for Therapeutic Purposes

International Journal of Molecular Sciences ◽

10.3390/ijms20020236 ◽

2019 ◽

Vol 20 (2) ◽

pp. 236 ◽

Cited By ~ 29

Author(s):

Claudia Campanella ◽

Celeste Caruso Bavisotto ◽

Mariantonia Logozzi ◽

Antonella Marino Gammazza ◽

Davide Mizzoni ◽

...

Keyword(s):

Regenerative Medicine ◽

Extracellular Vesicles ◽

Lipid Membrane ◽

Cell Communication ◽

Membrane Vesicles ◽

Free Form ◽

Target Cells ◽

Disease Biomarkers ◽

Cellular Source ◽

Therapeutic Molecules

Extracellular vesicles (EVs) are lipid membrane vesicles released by all human cells and are widely recognized to be involved in many cellular processes, both in physiological and pathological conditions. They are mediators of cell-cell communication, at both paracrine and systemic levels, and therefore they are active players in cell differentiation, tissue homeostasis, and organ remodeling. Due to their ability to serve as a cargo for proteins, lipids, and nucleic acids, which often reflects the cellular source, they should be considered the future of the natural nanodelivery of bio-compounds. To date, natural nanovesicles, such as exosomes, have been shown to represent a source of disease biomarkers and have high potential benefits in regenerative medicine. Indeed, they deliver both chemical and bio-molecules in a way that within exosomes drugs are more effective that in their exosome-free form. Thus, to date, we know that exosomes are shuttle disease biomarkers and probably the most effective way to deliver therapeutic molecules within target cells. However, we do not know exactly which exosomes may be used in therapy in avoiding side effects as well. In regenerative medicine, it will be ideal to use autologous exosomes, but it seems not ideal to use plasma-derived exosomes, as they may contain potentially dangerous molecules. Here, we want to present and discuss a contradictory relatively unmet issue that is the lack of a general agreement on the choice for the source of extracellular vesicles for therapeutic use.

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Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

Antioxidants ◽

10.3390/antiox9080705 ◽

2020 ◽

Vol 9 (8) ◽

pp. 705 ◽

Cited By ~ 1

Author(s):

Beatriz Martins ◽

Madania Amorim ◽

Flávio Reis ◽

António Francisco Ambrósio ◽

Rosa Fernandes

Keyword(s):

Diabetic Retinopathy ◽

Extracellular Vesicles ◽

Vision Loss ◽

Current Knowledge ◽

Critical Role ◽

Cell Communication ◽

Cell Junctions ◽

Low Grade ◽

Long Distance ◽

Advanced Stages

Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.

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The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

Cancers ◽

10.3390/cancers13164004 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4004

Author(s):

Michael O’Rawe ◽

Ethan J. Kilmister ◽

Theo Mantamadiotis ◽

Andrew H. Kaye ◽

Swee T. Tan ◽

...

Keyword(s):

Tumor Microenvironment ◽

Critical Role ◽

Tumor Development ◽

Renin Angiotensin System ◽

Cost Effective ◽

Therapy Resistance ◽

Current Standard ◽

Angiotensin System ◽

Renin Angiotensin ◽

Therapeutic Alternative

Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB.

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The key roles of cancer stem cell-derived extracellular vesicles

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00499-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Chaoyue Su ◽

Jianye Zhang ◽

Yosef Yarden ◽

Liwu Fu

Keyword(s):

Tumor Progression ◽

Extracellular Vesicles ◽

Significant Contribution ◽

Tumor Development ◽

Cell Communication ◽

Tumor Resistance ◽

Self Renewal ◽

Key Factor ◽

Tumor Immunosuppression ◽

New Ideas

AbstractCancer stem cells (CSCs), the subpopulation of cancer cells, have the capability of proliferation, self-renewal, and differentiation. The presence of CSCs is a key factor leading to tumor progression and metastasis. Extracellular vesicles (EVs) are nano-sized particles released by different kinds of cells and have the capacity to deliver certain cargoes, such as nucleic acids, proteins, and lipids, which have been recognized as a vital mediator in cell-to-cell communication. Recently, more and more studies have reported that EVs shed by CSCs make a significant contribution to tumor progression. CSCs-derived EVs are involved in tumor resistance, metastasis, angiogenesis, as well as the maintenance of stemness phenotype and tumor immunosuppression microenvironment. Here, we summarized the molecular mechanism by which CSCs-derived EVs in tumor progression. We believed that the fully understanding of the roles of CSCs-derived EVs in tumor development will definitely provide new ideas for CSCs-based therapeutic strategies.

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Distinct Cargos of Small Extracellular Vesicles Derived from Hypoxic Cells and Their Effect on Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21145071 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5071

Author(s):

Geoffroy Walbrecq ◽

Christiane Margue ◽

Iris Behrmann ◽

Stephanie Kreis

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Solid Tumors ◽

Extracellular Vesicles ◽

Biological Effects ◽

Biological Molecules ◽

Distant Future ◽

Poor Outcome ◽

Metastatic Sites

Hypoxia is a common hallmark of solid tumors and is associated with aggressiveness, metastasis and poor outcome. Cancer cells under hypoxia undergo changes in metabolism and there is an intense crosstalk between cancer cells and cells from the tumor microenvironment. This crosstalk is facilitated by small extracellular vesicles (sEVs; diameter between 30 and 200 nm), including exosomes and microvesicles, which carry a cargo of proteins, mRNA, ncRNA and other biological molecules. Hypoxia is known to increase secretion of sEVs and has an impact on the composition of the cargo. This sEV-mediated crosstalk ultimately leads to various biological effects in the proximal tumor microenvironment but also at distant, future metastatic sites. In this review, we discuss the changes induced by hypoxia on sEV secretion and their cargo as well as their effects on the behavior and metabolism of cancer cells, the tumor microenvironment and metastatic events.

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MicroRNAs: Their Role in Metabolism, Tumor Microenvironment, and Therapeutic Implications in Head and Neck Squamous Cell Carcinoma

Cancers ◽

10.3390/cancers13225604 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5604

Author(s):

Shine-Gwo Shiah ◽

Sung-Tau Chou ◽

Jang-Yang Chang

Keyword(s):

Tumor Microenvironment ◽

Epithelial Mesenchymal Transition ◽

Tumor Development ◽

Cell Communication ◽

Cell Types ◽

Metabolic Reprogramming ◽

Mesenchymal Transition ◽

Therapeutic Implications ◽

Rna Molecules ◽

Non Coding Rna

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that negatively regulate gene expression by binding to target mRNAs. Deregulated miRNAs can act as either oncogenic miRNAs or tumor suppressor miRNAs in controlling proliferation, differentiation, apoptosis, metastasis, epithelial–mesenchymal transition, and immune responses, which are all involved in the carcinogenesis process of HNSCC. Recent findings have shown that metabolic reprogramming is an important hallmark of cancer, which is necessary for malignant transformation and tumor development. Some reprogrammed metabolisms are believed to be required for HNSCC against an unfavorable tumor microenvironment (TME). The TME is composed of various cell types embedded in the altered extracellular matrix, among which exosomes, secreted by cancer cells, are one of the most important factors. Tumor-derived exosomes reshape the tumor microenvironment and play a crucial role in cell-to-cell communication during HNSCC development. Exosomes encapsulate many biomolecules, including miRNAs, circulate in body fluids, and can transmit intercellular regulatory messages to nearby and distant sites, which indicates that exosomal miRNAs have the potential to become non-invasive biomarkers. This review aims to clarify the functions of diverse miRNAs in HNSCC metabolic reprogramming and tumor-derived exosomes. In addition, it also emphasizes the potential role of miRNA as a biomarker in the diagnosis, prognosis, and treatment of HNSCC cancer.

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An Insight into the Roles of MicroRNAs and Exosomes in Sarcoma

Cancers ◽

10.3390/cancers11030428 ◽

2019 ◽

Vol 11 (3) ◽

pp. 428 ◽

Cited By ~ 6

Author(s):

Isaku Kohama ◽

Nobuyoshi Kosaka ◽

Hirotaka Chikuda ◽

Takahiro Ochiya

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Solid Tumors ◽

Extracellular Vesicles ◽

Noncoding Rna ◽

Premetastatic Niche ◽

Related Disease ◽

Distant Organ ◽

Insight Into

Sarcomas are rare solid tumors, but at least one-third of patients with sarcoma die from tumor-related disease. MicroRNA (miRNA) is a noncoding RNA that regulates gene expression in all cells and plays a key role in the progression of cancers. Recently, it was identified that miRNAs are transferred between cells by enclosure in extracellular vesicles, especially exosomes. The exosome is a 100 nm-sized membraned vesicle that is secreted by many kinds of cells and contains miRNA, mRNA, DNA, and proteins. Cancer uses exosomes to influence not only the tumor microenvironment but also the distant organ to create a premetastatic niche. The progression of sarcoma is also regulated by miRNAs and exosomes. These miRNAs and exosomes can be targeted as biomarkers and treatments. In this review, we summarize the studies of miRNA and exosomes in sarcoma.

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Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity

Cancers ◽

10.3390/cancers12010171 ◽

2020 ◽

Vol 12 (1) ◽

pp. 171 ◽

Cited By ~ 8

Author(s):

Donatella Lucchetti ◽

Claudio Ricciardi Tenore ◽

Filomena Colella ◽

Alessandro Sgambato

Keyword(s):

Tumor Microenvironment ◽

Cancer Cells ◽

Cell Fate ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Cell Communication ◽

Metabolic Effects ◽

Metabolic Phenotype ◽

Metabolic Switch

A better understanding of the mechanisms of cell communication between cancer cells and the tumor microenvironment is crucial to develop personalized therapies. It has been known for a while that cancer cells are metabolically distinct from other non-transformed cells. This metabolic phenotype is not peculiar to cancer cells but reflects the characteristics of the tumor microenvironment. Recently, it has been shown that extracellular vesicles are involved in the metabolic switch occurring in cancer and tumor-stroma cells. Moreover, in an immune system, the metabolic programs of different cell subsets are distinctly associated with their immunological function, and extracellular vesicles could be a key factor in the shift of cell fate modulating cancer immunity. Indeed, during tumor progression, tumor-associated immune cells and fibroblasts acquire a tumor-supportive and anti-inflammatory phenotype due to their interaction with tumor cells and several findings suggest a role of extracellular vesicles in this phenomenon. This review aims to collect all the available evidence so far obtained on the role of extracellular vesicles in the modulation of cell metabolism and immunity. Moreover, we discuss the possibility for extracellular vesicles of being involved in drug resistance mechanisms, cancer progression and metastasis by inducing immune-metabolic effects on surrounding cells.

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Ovarian-Cancer-Associated Extracellular Vesicles: Microenvironmental Regulation and Potential Clinical Applications

Cells ◽

10.3390/cells10092272 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2272

Author(s):

Priyakshi Kalita-de Croft ◽

Shayna Sharma ◽

Nihar Godbole ◽

Gregory E. Rice ◽

Carlos Salomon

Keyword(s):

Ovarian Cancer ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cell Function ◽

Early Stage ◽

Cell Communication ◽

Therapeutic Agents ◽

Cell Of Origin ◽

Wide Range

Ovarian cancer (OC) is one of the most diagnosed gynecological cancers in women. Due to the lack of effective early stage screening, women are more often diagnosed at an advanced stage; therefore, it is associated with poor patient outcomes. There are a lack of tools to identify patients at the highest risk of developing this cancer. Moreover, early detection strategies, therapeutic approaches, and real-time monitoring of responses to treatment to improve survival and quality of life are also inadequate. Tumor development and progression are dependent upon cell-to-cell communication, allowing cancer cells to re-program cells not only within the surrounding tumor microenvironment, but also at distant sites. Recent studies established that extracellular vesicles (EVs) mediate bi-directional communication between normal and cancerous cells. EVs are highly stable membrane vesicles that are released from a wide range of cells, including healthy and cancer cells. They contain tissue-specific signaling molecules (e.g., proteins and miRNA) and, once released, regulate target cell phenotypes, inducing a pro-tumorigenic and immunosuppressive phenotype to contribute to tumor growth and metastasis as well as proximal and distal cell function. Thus, EVs are a “fingerprint” of their cell of origin and reflect the metabolic status. Additionally, via the capacity to evade the immune system and remain stable over long periods in circulation, EVs can be potent therapeutic agents. This review examines the potential role of EVs in the different aspects of the tumor microenvironment in OC, as well as their application in diagnosis, delivery of therapeutic agents, and disease monitoring.

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Extracellular Vesicles: A New Perspective in Tumor Therapy

BioMed Research International ◽

10.1155/2018/2687954 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Yan-Zi Sun ◽

Jun-Shan Ruan ◽

Zong-Sheng Jiang ◽

Ling Wang ◽

Shao-Ming Wang

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Therapy ◽

Tumor Therapy ◽

Critical Role ◽

Mesenchymal Transition

In recent years, the study of extracellular vesicles has been booming across various industries. Extracellular vesicles are considered one of the most important physiological endogenous carriers for the specific delivery of molecular information (nucleonic acid, cytokines, enzymes, etc.) between cells. It has been discovered that they perform a critical role in promoting tumor cell growth, proliferation, tumor cell invasion, and metastatic ability and regulating the tumor microenvironment to promote tumor cell communication and metastasis. In this review, we will discuss (1) the mechanism of extracellular vesicles generation, (2) their role in tumorigenesis and cancer progression (cell growth and proliferation, tumor microenvironment, epithelial-mesenchymal transition (EMT), invasion, and metastasis), (3) the role of extracellular vesicles in immune therapy, (4) extracellular vesicles targeting in tumor therapy, and (5) the role of extracellular vesicles as biomarkers. It is our hope that better knowledge and understanding of the extracellular vesicles will offer a wider range of effective therapeutic targets for experimental tumor research.

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