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 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 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 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 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.

scholarly journals TAMI-05. THE IRRADIATED BRAIN MICROENVIRONMENT SUPPORTS GLIOMA STEMNESS AND SURVIVAL VIA ASTROCYTE-DERIVED TRANSGLUTAMINASE 2

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii213-ii214
Author(s):  
Tracy Berg ◽  
Carolina Marques ◽  
Vasiliki Pantazopoulou ◽  
Elinn Johansson ◽  
Kristoffer von Stedingk ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Mouse Models ◽  
Transglutaminase 2 ◽  
Standard Of Care ◽  
High Dose ◽  
Primary Tumors ◽  
The Impact ◽  
The Brain

Abstract The highest-grade gliomas invariably recur as incurable tumors following standard of care comprising surgery, radiotherapy, and chemotherapy. The majority of the recurrent tumors form within the area of the brain receiving high-dose irradiation during treatment of the primary tumor, indicating that the recurrent tumor forms in an irradiated microenvironment. The tumor microenvironment has been demonstrated to influence the therapeutic response and stemness characteristics of tumor cells, but the influence of radiation on the microenvironment and its subsequent consequences for tumor cells are incompletely understood. Here, we used genetically engineered glioma mouse models and human glioma samples to characterize the impact of standard of care radiotherapy on the brain tumor microenvironment. We found that tumor-associated astrocytes subjected to radiation in vitro could enhance tumor cell stemness and survival of co-cultured glioma cells. More aggressive gliomas formed in vivo when mouse brains were irradiated prior to tumor cell implantation, suggesting that the irradiated brain microenvironment supports tumor growth. We isolated the effect of irradiated astrocytes to extracellular matrix secreted by these cells, and specifically found that astrocyte-derived transglutaminase 2 (TGM2) is a stromal promoter of glioma stemness and radioresistance. TGM2 levels were increased after radiation in glioma mouse models. Recombinant TGM2 enhanced, and TGM2 inhibitors blocked, glioma cell stemness. In human GBM tissue, TGM2 levels were increased in recurrent vs. primary tumors. In summary, in addition to supporting TGM2 as a potential therapeutic target in glioma, our data indicate that radiotherapy results in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.

scholarly journals Exosomes and Their Role in Cancer Progression

2021 ◽  
Vol 11 ◽  
Author(s):  
Yang Liu ◽  
Ke Shi ◽  
Yong Chen ◽  
Xianrui Wu ◽  
Zheng Chen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Research Progress ◽  
Chemotherapeutic Drugs ◽  
Other Substances

Exosomes from extracellular vesicles can activate or inhibit various signaling pathways by transporting proteins, lipids, nucleic acids and other substances to recipient cells. In addition, exosomes are considered to be involved in the development and progression of tumors from different tissue sources in numerous ways, including remodeling of the tumor microenvironment, promoting angiogenesis, metastasis, and invasion, and regulating the immune escape of tumor cells. However, the precise molecular mechanisms by which exosomes participate in these different processes remains unclear. In this review, we describe the research progress of tumor cell-derived exosomes in cancer progression. We also discuss the prospects of the application of exosomes combined with nanoengineered chemotherapeutic drugs in the treatment of cancer.

Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?

2014 ◽  
Vol 10 (01) ◽  
pp. 13 ◽  
Author(s):  
Thomas N Seyfried ◽  
Jeremy Marsh ◽  
Purna Mukherjee ◽  
Giulio Zuccoli ◽  
Dominic P D’Agostino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Standard Of Care ◽  
Viable Alternative ◽  
Cell Subpopulation ◽  
Normal Brain ◽  
Current Standard ◽  
Metabolic Therapy ◽  
Ketogenic Diets

Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (β-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.

Could Metabolic Therapy Become a Viable Alternative to the Standard of Care for Managing Glioblastoma?

US Neurology ◽  
2014 ◽  
Vol 10 (01) ◽  
pp. 48 ◽  
Author(s):  
Thomas N Thomas N ◽  
Jeremy Marsh ◽  
Purna Mukherjee ◽  
Giulio Zuccoli ◽  
Dominic P D’Agostino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Standard Of Care ◽  
Viable Alternative ◽  
Cell Subpopulation ◽  
Normal Brain ◽  
Current Standard ◽  
Metabolic Therapy ◽  
Ketogenic Diets

Little progress has been made in the long-term management of glioblastoma multiforme (GBM) for more than 40 years. The current standard of care (SOC) for GBM involves radiotherapy with concomitant adjuvant temozolomide chemotherapy. Perioperative corticosteroids are also administered to the majority of GBM patients. The current standard treatment strategy for GBM increases availability of glucose (from steroids) and glutamine (from radio-necrosis) in the tumor microenvironment. Emerging evidence indicates that GBM, like most cancers, is a metabolic disease displaying a robust Warburg effect. It is well documented that glucose and glutamine are major metabolic fuels that drive tumor progression. Recent evidence suggests that neoplastic cells with macrophage/microglia properties can contribute to the most invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells as well as for the more rapidly proliferating cancer cells. Metabolic therapy exploits the biological differences between tumor cells and normal cells for the non-toxic targeting of the tumor cells. Studies in preclinical models show that calorie restricted ketogenic diets (KD-R), anti-glycolytic drugs, and hyperbaric oxygen therapy can reduce availability of glucose and glutamine in the tumor microenvironment while enhancing oxidative stress in tumor cells. The predominant ketone body (b-hydroxybutyrate) reduces oxidative stress in normal brain cells. The potential success of metabolic therapy was also seen in human glioma case studies suggesting that this therapeutic strategy could become a viable alternative to the SOC.

scholarly journals Role of Exosomes in Prostate Cancer Metastasis

2021 ◽  
Vol 22 (7) ◽  
pp. 3528
Author(s):  
Theresa Akoto ◽  
Sharanjot Saini
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Intercellular Communication ◽  
Cancer Metastasis ◽  
Disseminated Tumor Cells ◽  
Bilayer Membrane ◽  
Prostate Cancer Progression ◽  
Prostate Cancer Metastasis

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.

Sign in / Sign up

Export Citation Format

Share Document