scholarly journals Critical Roles of Tumor Extracellular Vesicles in the Microenvironment of Thoracic Cancers

2020 ◽  
Vol 21 (17) ◽  
pp. 6024
Author(s):  
Lyna Kara-Terki ◽  
Lucas Treps ◽  
Christophe Blanquart ◽  
Delphine Fradin
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Special Focus ◽  
Pleural Mesothelioma ◽  
Lung Cancers ◽  
Non Coding Rna ◽  
Exosomal Mirnas ◽  
Tumor Growth And Metastasis

Extracellular vesicles (EVs), such as exosomes, are critical mediators of intercellular communication between tumor cells and other cells located in the microenvironment but also in more distant sites. Exosomes are small EVs that can carry a variety of molecules, such as lipids, proteins, and non-coding RNA, especially microRNAs (miRNAs). In thoracic cancers, including lung cancers and malignant pleural mesothelioma, EVs contribute to the immune-suppressive tumor microenvironment and to tumor growth and metastasis. In this review, we discuss the recent understanding of how exosomes behave in thoracic cancers and how and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy, with a special focus on exosomal miRNAs.

scholarly journals Extracellular Vesicles in Reprogramming of the Ewing Sarcoma Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Manideep C. Pachva ◽  
Horton Lai ◽  
Andy Jia ◽  
Melanie Rouleau ◽  
Poul H. Sorensen
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Metastatic Disease ◽  
Ewing Sarcoma ◽  
Intercellular Communication ◽  
Clinical Intervention ◽  
Standard Of Care ◽  
Systemic Circulation ◽  
Stromal Fibroblast

Ewing sarcoma (EwS) is a highly aggressive cancer and the second most common malignant bone tumor of children and young adults. Although patients with localized disease have a survival rate of approximately 75%, the prognosis for patients with metastatic disease remains dismal (<30%) and has not improved in decades. Standard-of-care treatments include local therapies such as surgery and radiotherapy, in addition to poly-agent adjuvant chemotherapy, and are often associated with long-term disability and reduced quality of life. Novel targeted therapeutic strategies that are more efficacious and less toxic are therefore desperately needed, particularly for metastatic disease, given that the presence of metastasis remains the most powerful predictor of poor outcome in EwS. Intercellular communication within the tumor microenvironment is emerging as a crucial mechanism for cancer cells to establish immunosuppressive and cancer-permissive environments, potentially leading to metastasis. Altering this communication within the tumor microenvironment, thereby preventing the transfer of oncogenic signals and molecules, represents a highly promising therapeutic strategy. To achieve this, extracellular vesicles (EVs) offer a candidate mechanism as they are actively released by tumor cells and enriched with proteins and RNAs. EVs are membrane-bound particles released by normal and tumor cells, that play pivotal roles in intercellular communication, including cross-talk between tumor, stromal fibroblast, and immune cells in the local tumor microenvironment and systemic circulation. EwS EVs, including the smaller exosomes and larger microvesicles, have the potential to reprogram a diversity of cells in the tumor microenvironment, by transferring various biomolecules in a cell-specific manner. Insights into the various biomolecules packed in EwS EVs as cargos and the molecular changes they trigger in recipient cells of the tumor microenvironment will shed light on various potential targets for therapeutic intervention in EwS. This review details EwS EVs composition, their potential role in metastasis and in the reprogramming of various cells of the tumor microenvironment, and the potential for clinical intervention.

scholarly journals Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1450 ◽  
Author(s):  
Patrick Santos ◽  
Fausto Almeida
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Therapy Resistance ◽  
Chemotherapeutic Agents ◽  
Exosomal Mirnas ◽  
Key Factor

Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field.

scholarly journals The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 93 ◽  
Author(s):  
James Jabalee ◽  
Rebecca Towle ◽  
Cathie Garnis
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Tumor Stroma ◽  
Therapeutic Implications ◽  
Membrane Bound ◽  
Immune Destruction ◽  
And Function ◽  
Cargo Molecule

Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound structures that play key roles in intercellular communication. EVs are potent regulators of tumorigenesis and function largely via the shuttling of cargo molecules (RNA, DNA, protein, etc.) among cancer cells and the cells of the tumor stroma. EV-based crosstalk can promote proliferation, shape the tumor microenvironment, enhance metastasis, and allow tumor cells to evade immune destruction. In many cases these functions have been linked to the presence of specific cargo molecules. Herein we will review various types of EV cargo molecule and their functional impacts in the context of oncology.

scholarly journals The Complicated Effects of Extracellular Vesicles and Their Cargos on Embryo Implantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Nan-Xing Jiang ◽  
Xue-Lian Li
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Embryo Implantation ◽  
Implantation Failure ◽  
Rate Limiting Step ◽  
Non Coding Rna ◽  
Long Non Coding Rna

As a rate-limiting step in pregnancy, embryo implantation is highly dependent on intercellular communication. Extracellular vesicles (EVs) are newly identified to be important in the course of intercellular communication. EVs have been isolated from a wide variety of biofluids and tissues, including plasma, liver, uterine, semen, embryo, etc. The present and future use of EVs not only as biomarkers, but also as targeting drug delivery system, is promisingly pave the way for advanced comprehension of implantation failure in reproductive diseases. However, as the precise mechanisms of EVs in embryo implantation has not been elucidated yet. Herein, we summarize the current knowledge on the diverse effects of EVs from various sources and their cargos such as microRNA, long non-coding RNA, protein, etc. on embryo implantation, and the potential mechanisms of EVs in reproductive diseases such as recurrent implantation failure, polycystic ovary syndrome and endometriosis. It is essential to note that many of the biologically plausible functions of EVs in embryo implantation discussed in present literatures still need further research in vivo.

scholarly journals Intercellular transfer of mitochondrial DNA carrying metastasis-enhancing pathogenic mutations from high- to low-metastatic tumor cells and stromal cells via extracellular vesicles

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Keizo Takenaga ◽  
Nobuko Koshikawa ◽  
Hiroki Nagase
Keyword(s):  
Mitochondrial Dna ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Metastatic Tumor ◽  
Dependent Manner ◽  
Intercellular Transfer ◽  
Pathogenic Mutations ◽  
Metastatic Cells

Abstract Background Mitochondrial DNA (mtDNA) carrying certain pathogenic mutations or single nucleotide variants (SNVs) enhances the invasion and metastasis of tumor cells, and some of these mutations are homoplasmic in tumor cells and even in tumor tissues. On the other hand, intercellular transfer of mitochondria and cellular components via extracellular vesicles (EVs) and tunneling nanotubes (TNTs) has recently attracted intense attention in terms of cell-to-cell communication in the tumor microenvironment. It remains unclear whether metastasis-enhancing pathogenic mutant mtDNA in tumor cells is intercellularly transferred between tumor cells and stromal cells. In this study, we investigated whether mtDNA with the NADH dehydrogenase subunit 6 (ND6) G13997A pathogenic mutation in highly metastatic cells can be horizontally transferred to low-metastatic cells and stromal cells in the tumor microenvironment. Results When MitoTracker Deep Red-labeled high-metastatic Lewis lung carcinoma A11 cells carrying the ND6 G13997A mtDNA mutation were cocultured with CellLight mitochondria-GFP-labeled low-metastatic P29 cells harboring wild-type mtDNA, bidirectional transfer of red- and green-colored vesicles, probably mitochondria-related EVs, was observed in a time-dependent manner. Similarly, intercellular transfer of mitochondria-related EVs occurred between A11 cells and α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs, WA-mFib), macrophages (RAW264.7) and cytotoxic T cells (CTLL-2). Intercellular transfer was suppressed by inhibitors of EV release. The large and small EV fractions (L-EV and S-EV, respectively) prepared from the conditioned medium by differential ultracentrifugation both were found to contain mtDNA, although only S-EVs were efficiently incorporated into the cells. Several subpopulations had evidence of LC3-II and contained degenerated mitochondrial components in the S-EV fraction, signaling to the existence of autophagy-related S-EVs. Interestingly, the S-EV fraction contained a MitoTracker-positive subpopulation, which was inhibited by the respiration inhibitor antimycin A, indicating the presence of mitochondria with membrane potential. It was also demonstrated that mtDNA was transferred into mtDNA-less ρ0 cells after coculture with the S-EV fraction. In syngeneic mouse subcutaneous tumors formed by a mixture of A11 and P29 cells, the mitochondria-related EVs released from A11 cells reached distantly positioned P29 cells and CAFs. Conclusions These results suggest that metastasis-enhancing pathogenic mtDNA derived from metastatic tumor cells is transferred to low-metastatic tumor cells and stromal cells via S-EVs in vitro and in the tumor microenvironment, inferring a novel mechanism of enhancement of metastatic potential during tumor progression.

scholarly journals The Interaction Between Long Non-Coding RNAs and Cancer-Associated Fibroblasts in Lung Cancer

2022 ◽  
Vol 9 ◽  
Author(s):  
Wenqi Ti ◽  
Jianbo Wang ◽  
Yufeng Cheng
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Cancer Associated Fibroblasts ◽  
Protein Coding ◽  
Sequencing Technologies ◽  
Integral Role ◽  
Tumor Growth And Metastasis

Despite great advances in research and treatment, lung cancer is still one of the most leading causes of cancer-related deaths worldwide. Evidence is mounting that dynamic communication network in the tumor microenvironment (TME) play an integral role in tumor initiation and development. Cancer-associated fibroblasts (CAFs), which promote tumor growth and metastasis, are the most important stroma component in the tumor microenvironment. Consequently, in-depth identification of relevant molecular mechanisms and biomarkers related to CAFs will increase understanding of tumor development process, which is of great significance for precise treatment of lung cancer. With the development of sequencing technologies such as microarray and next-generation sequencing, lncRNAs without protein-coding ability have been found to act as communicators between tumor cells and CAFs. LncRNAs participate in the activation of normal fibroblasts (NFs) to CAFs. Moreover, activated CAFs can influence the gene expression and secretion characteristics of cells through lncRNAs, enhancing the malignant biological process in tumor cells. In addition, lncRNA-loaded exosomes are considered to be another important form of crosstalk between tumor cells and CAFs. In this review, we focus on the interaction between tumor cells and CAFs mediated by lncRNAs in the lung cancer microenvironment, and discuss the analysis of biological function and molecular mechanism. Furthermore, it contributes to paving a novel direction for the clinical treatment of lung cancer.

scholarly journals Subverting Subversion: A Review on the Breast Cancer Microenvironment and Therapeutic Opportunities

2015 ◽  
Vol 9s2 ◽  
pp. BCBCR.S29423 ◽  
Author(s):  
Ethan Rothschild ◽  
Debabrata Banerjee
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Adaptive Immune Response ◽  
Suppressor Cells ◽  
Cancer Cell Growth ◽  
Chemotherapy Drugs ◽  
Tumor Growth And Metastasis ◽  
Novel Target

This review combines the recent research on the subject of tumor immunology and methods of correcting the immune system's reaction to the tumor microenvironment while impeding the survival and growth of tumor cells, with a focus on breast cancer. Induction of hypoxia-inducible genes in the microenvironment leads to lowering of its pH. This impedes the adaptive immune response and acts to recruit cells of the immune system, which suppress the immune response. Regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs), and their derivatives coordinate an anti-autoimmunity response and a healing response in concert with tumor-secreted cytokines, enzymes, and antigens. Together, they suppress a proper immune reaction to tumor cells and promote cellular reproduction ( Fig. 1 ). In addition, the hypoxia-inducible response and components of the tumor microenvironment such as cancer-associated fibroblasts (CAFs) also create an ideal environment for tumor growth and metastasis via neoangiogenesis and increased motility. Broad-spectrum chemotherapy drugs are problematic as breast cancer cells develop resistance through selective loss of a novel target and downregulation of apoptotic factors. A better understanding of the tumor microenvironment offers new therapeutic opportunities to rescue the immune response, inhibit cancer cell growth pathways, and subvert the tumor microenvironment with little toxicity and side effects.

scholarly journals Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets

2020 ◽  
Vol 21 (18) ◽  
pp. 6680 ◽  
Author(s):  
Takaaki Tamura ◽  
Yusuke Yoshioka ◽  
Shinichi Sakamoto ◽  
Tomohiko Ichikawa ◽  
Takahiro Ochiya
Keyword(s):  
Bone Metastasis ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Novel Treatments ◽  
Biological Phenomena ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Extracellular vesicles (EVs) are lipid membranous vesicles that are released from every type of cell. It has become clear that EVs are involved in a variety of biological phenomena, including cancer progression, and play critical roles in intracellular communication through the horizontal transfer of cellular cargoes such as proteins, DNA fragments, RNAs including mRNA and non-coding RNAs (microRNA, piRNA, and long non-coding RNA) and lipids. The most common cause of death associated with cancer is metastasis. Recent investigations have revealed that EVs are deeply associated with metastasis. Bone is a preferred site of metastasis, and bone metastasis is generally incurable and dramatically affects patient quality of life. Bone metastasis can cause devastating complications, including hypercalcemia, pathological fractures, spinal compression, and bone pain, which result in a poor prognosis. Although the mechanisms underlying bone metastasis have yet to be fully elucidated, increasing evidence suggests that EVs in the bone microenvironment significantly contribute to cancer progression and cancer bone tropism. Emerging evidence on EV functions in bone metastasis will facilitate the discovery of novel treatments. In this review, we will discuss the remarkable effects of EVs, especially on the tumor microenvironment in bone.

scholarly journals Exosomes in Immune Regulation

2021 ◽  
Vol 7 (1) ◽  
pp. 4
Author(s):  
Heidi Schwarzenbach ◽  
Peter B. Gahan
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Immune Cells ◽  
Intercellular Communication ◽  
Immune Regulation ◽  
Immune Escape ◽  
Cytotoxic Responses

Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor.

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