Cancer Extracellular Vesicles, Tumoroid Models, and Tumor Microenvironment

2022 ◽  
Author(s):  
Takanori Eguchi ◽  
Mona Sheta ◽  
Masanori Fujii ◽  
Stuart K. Calderwood
Keyword(s):  
Tumor Microenvironment ◽  
Extracellular Vesicles

scholarly journals 695 Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Loise Francisco-Anderson ◽  
Loise Francisco-Anderson ◽  
Mary Abdou ◽  
Michael Goldberg ◽  
Erin Troy ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Extracellular Vesicle ◽  
The Body ◽  
Checkpoint Inhibition ◽  
Small Intestinal ◽  
The Impact

BackgroundThe small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity preclinically via pattern recognition receptor-mediated activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition.MethodsEDP1908 is a preparation of extracellular vesicles produced by a gram-stain negative strain of bacterium of the Oscillospiraceae family isolated from a human donor. EDP1908 was selected for its immunostimulatory profile in a screen of EVs from a range of distinct microbial strains. Its mechanism of action was determined by ex vivo analysis of the tumor microenvironment (TME) and by in vitro functional studies with murine and human cells.ResultsOral treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to checkpoint inhibition (anti-PD-1) or an intact microbe. EDP1908 significantly increased the percentage of IFNγ and TNF producing CD8+ CTLs, NK cells, NKT cells and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increased tumor-infiltrating dendritic cells (DC1 and DC2). Analysis of cytokines in the TME showed significant increases in IP-10 and IFNg production in mice treated with EDP1908, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes.ConclusionsThis is the first report of striking anti-tumor effects of an orally delivered microbial extracellular vesicle. These data point to oral EVs as a new class of immunotherapeutic drugs. They are particularly effective at harnessing the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.Ethics ApprovalPreclinical murine studies were conducted under the approval of the Avastus Preclinical Services’ Ethics Board. Human in vitro samples were attained by approval of the IntegReview Ethics Board; informed consent was obtained from all subjects.

scholarly journals The Role of Extracellular Vesicles in the Development of a Cancer Stem Cell Microenvironment Niche and Potential Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2435
Author(s):  
Thomas J. Brown ◽  
Victoria James
Keyword(s):  
Systematic Review ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Multiple Cancer ◽  
Therapeutic Targeting ◽  
Small Component ◽  
Facilitated Communication ◽  
Cell Microenvironment ◽  
Cancer Types

Cancer stem cells (CSCs) have increasingly been shown to be a crucial element of heterogenous tumors. Although a relatively small component of the population, they increase the resistance to treatment and the likelihood of recurrence. In recent years, it has been shown, across multiple cancer types (e.g., colorectal, breast and prostate), that reciprocal communication between cancer and the microenvironment exists, which is, in part, facilitated by extracellular vesicles (EVs). However, the mechanisms of this method of communication and its influence on CSC populations is less well-understood. Therefore, the aim of this systematic review is to determine the evidence that supports the role of EVs in the manipulation of the tumor microenvironment to promote the survival of CSCs. Embase and PubMed were used to identify all studies on the topic, which were screened using PRISMA guidelines, resulting in the inclusion of 16 studies. These 16 studies reported on the EV content, pathways altered by EVs and therapeutic targeting of CSC through EV-mediated changes to the microenvironment. In conclusion, these studies demonstrated the role of EV-facilitated communication in maintaining CSCs via manipulation of the tumor microenvironment, demonstrating the potential of creating therapeutics to target CSCs. However, further works are needed to fully understand the targetable mechanisms upon which future therapeutics can be based.

scholarly journals Gastric Cancer Extracellular Vesicles Tune the Migration and Invasion of Epithelial and Mesenchymal Cells in a Histotype-Dependent Manner

2019 ◽  
Vol 20 (11) ◽  
pp. 2608 ◽  
Author(s):  
Sara Rocha ◽  
Sara Pinto Teles ◽  
Mafalda Azevedo ◽  
Patrícia Oliveira ◽  
Joana Carvalho ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Flow Cytometry ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Mesenchymal Cells ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Diffuse Type ◽  
Transmission Electron

Extracellular vesicles (EVs) secreted by tumor cells modulate recipient cells’ behavior, but their effects in normal cells from the tumor microenvironment remain poorly known. In this study, we dissected the functional impact of gastric cancer cell-derived EVs (GC-EVs), representative of distinct GC histotypes, on the behavior of normal isogenic epithelial and mesenchymal cells. GC-EVs were isolated by differential centrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and imaging flow-cytometry. Epithelial and mesenchymal cells were challenged with GC-EVs and submitted to proliferation, migration, and invasion assays. Expression of epithelial and mesenchymal markers was followed by immunofluorescence and flow-cytometry. Our results indicated that GC-EVs secreted by diffuse-type cancer cells decrease the migration of recipient cells. This effect was more prominent and persistent for mesenchymal recipient cells, which also increased Fibronectin expression in response to EVs. GC-EVs secreted by cancer cells derived from tumors with an intestinal component increased invasion of recipient epithelial cells, without changes in EMT markers. In summary, this study demonstrated that GC-EVs modulate the migration and invasion of epithelial and mesenchymal cells from the tumor microenvironment, in a histotype-dependent manner, highlighting new features of intestinal and diffuse-type GC cells, which may help explaining differential metastasis patterns and aggressiveness of GC histotypes.

scholarly journals TMIC-56. ROLE OF HUMAN BRAIN TUMOR STEM CELLS-DERIVED EXTRACELLULAR VESICLES ON THE PHENOTYPIC TRANSDIFFERENTIATION OF HUMAN NEURAL PROGENITOR CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi260-vi260
Author(s):  
Natanael Zarco ◽  
Emily Norton ◽  
Montserrat Lara-Velazquez ◽  
Anna Carrano ◽  
Alfredo Quinones-Hinojosa ◽  
...  
Keyword(s):  
Stem Cells ◽  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Primary Cultures ◽  
Adult Brain ◽  
Cell Subpopulation ◽  
Tumor Stem Cells ◽  
Brain Tumor Stem Cells

Abstract Glioblastoma (GBM) is the most aggressive of all the brain tumors with a median patient survival less than 15 months. Despite of surgical resection, radiotherapy, and chemotherapy, recurrence rate is almost 100%. A great percentage of GBM tumors (~60%) infiltrate and contact the ventricular-subventricular zone (V-SVZ). Interestingly, these tumors are the most aggressive, and invariably lead to higher distal recurrence rates, shorter time to tumor progression, and lower overall survival of the patient. The reason for this role of V-SVZ-proximity on the outcome of GBM patients is unknown. We suggest that a potential explanation is the interaction of GBM with the V-SVZ. This region is the largest neurogenic niche in the adult brain where neural stem cells (NSCs) give rise to newborn neuroblasts that migrate toward the olfactory bulb. In GBM there is a cell subpopulation called brain tumor stem cells (BTSCs) with NSCs-like characteristics, but with added potential for tumor initiation, recurrence and invasiveness. Tumor microenvironment plays an important role in migration and invasion process. In the present work, we used the total exosome isolation kit to purify Extracellular Vesicles (EVs) from human primary cultures of BTSCs. We determined that BTSCs-derived EVs contain specific information that is transfer to primary cultures of human Neural Progenitors Cells (NPCs) modulating their proliferation rate, cell viability, and migration. In addition, we identify that NPCs taken up BTSCs-derived EVs and significantly increase the expression levels of stemness-related genes such as Nestin, Nanog, and Sox2, suggesting that a phenotypic transdifferentiation is being carry out. These results support our hypothesis that GBM modulate the tumor microenvironment close to the V-SVZ by releasing EVs that target cellular components in this region and promote their phenotypic transformation, highlighting that NPCs biology changes in the context of tumor environment.

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 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 Extracellular Vesicles: Evolving Factors in Stem Cell Biology

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Muhammad Nawaz ◽  
Farah Fatima ◽  
Krishna C. Vallabhaneni ◽  
Patrice Penfornis ◽  
Hadi Valadi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Cell Biology ◽  
Trophic Factors ◽  
Stem Cell Biology ◽  
Cell Fates ◽  
Bidirectional Communication

Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell-EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies.

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 P01.07 * IMPACT OF EXTRACELLULAR VESICLES RELEASED BY GLIOBLASTOMA CELLS AFTER IRRADIATION ON TUMOR MICROENVIRONMENT

2014 ◽  
Vol 16 (suppl 2) ◽  
pp. ii28-ii28
Author(s):  
H. Ding ◽  
S. Pinel ◽  
V. Jouan-Hureaux ◽  
A. Chateau ◽  
C. Boura ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Glioblastoma Cells
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