Functions and Therapeutic Roles of Exosomes in Cancer

Tickner, Jacob A; Urquhart, Aaron; Stephenson, Sally‐Anne; Richard, Derek J.; O’Byrne, Kenneth J.

doi:10.3389/fonc.2014.00127

Cited by 212 publications

(173 citation statements)

References 78 publications

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“…It has been noted that cancer cells secrete much higher amounts of exosomes in comparison to non-transformed cells (26). Exosomes are involved in initiation, growth, progression and drug-resistance of tumors involving interactions with the microenvironment by transferring oncogenic proteins and nucleic acids (15,19,27,28).…”

Section: Exosomes -Functions In Cancermentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

168

133

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Abstract. Exosomes are important contributors to cellMetastases are responsible for the death of a large majority of cancer patients despite considerable progress in surgical techniques, radiotherapy, chemotherapy and targeted therapies including immuno-therapy (1). A dramatic reduction of metastatic burden has been observed, however, tumor elimination is almost always incomplete. This phenomenon is based on drug resistance, which is due to adaptation of intracellular pathways or on activation of survival-supporting autocrine and paracrine pathways and several secreted factors expressed by drug-sensitive tumor cells after therapy (2). Metastasis can occur through release of cancer cells from the primary tumor into body cavities that holds true for ovarian and CNS tumors, or via hematogeneous and lymphatic vessels of the circulatory system (3). Metastases of some tumors are directed besides to lymph nodes to mainly one type of organ only, such as prostate cancer to the bones, pancreatic cancer and uveal melanoma to the liver, whereas tumors such as melanoma, breast-and lung cancer can colonize several types of organs (3). Tumor cells have been found in the blood of patients with early-stage cancer and in some cases even before the primary tumor has been diagnosed (4, 5). Recently, making use of single-cell expression profiling, it has been shown that early metastatic cells possess a stem-like gene signature and give rise to heterogeneous metastases (6). The metastatic process is characterized by a defined sequence of events (7,8). Initial steps are detachment from the extracellular matrix (ECM), invasion into the surrounding tissue and proteolysis of the basement membrane. After intravasation, survival of circulating tumor cells (CTCs) is achieved by forming clusters, binding to platelets and immune evasion. Subsequently, they arrest in distal microvascular beds and extravasation can be achieved either by migration through intercellular junctions of endothelial cells (EC) or penetration of a single EC (9). CTCs can also colonize their tumors of origin, a process referred to as "tumor self-seeding", selecting for cancer cell populations more aggressive than those present in the primary tumor (10). After extravasation, colonization and outgrowth in the parenchyma of distant organs are the following steps. A common theme of the metastatic process is settlement of disseminated tumor cells (DTCs) into latency (dormancy), which can last from several months to decades (11). It has been observed that DTCs are recruited into pre-metastatic niches that support their survival by interactions with endothelial, myeloid cells, fibroblasts and other types of cells. After adaptation to the host microenvironment and suppression of an anti-tumoral immune response, DTCs are activated by not yet completely resolved mechanisms. Finally their outgrowth is based on an angiogenic switch mediated by pro-angiogenic factors and establishment of a vascular network to support the metabolic demands of colonizing tumor cells (12). In the follo...

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Section: Exosomes -Functions In Cancermentioning

confidence: 99%

The Multiple Roles of Exosomes in Metastasis

Weidle

Birzele

Kollmorgen

et al. 2017

CGP

168

133

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“…Therefore, studies aiming to achieve cancer-derived exosome depletion from the circulation could be promising for the development of novel therapeutics that would mitigate tumor metastasis. 26,27 In this study, we demonstrated the therapeutic concept of suppressing cancer metastasis via the depletion of cancer-derived EVs. Antibodies to human-specific CD9 and CD63, which are considered to localize at the surface of most exosomes, 28 were utilized to inhibit the pro-metastatic effects of cancer-derived exosomes.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis

Nishida-Aoki¹,

Tominaga²,

et al. 2017

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Metastasis is the main cause of cancer mortality for many types of cancer; however, difficulties remain in effectively preventing metastasis. It has been recently and widely reported that cancer-derived extracellular vesicles (EVs) contribute to cancer metastasis. Thus, therapeutic strategies targeting cancerderived EVs hold great promise because of the possibility of EVs driving the cancer microenvironment toward metastasis. Here, we provide a novel strategy for therapeutic antibody treatment to target cancer-derived EVs and inhibit the metastasis of breast cancer in a mouse model, establishing a rationale for further clinical investigation. Treatment with human-specific anti-CD9 or anti-CD63 antibodies significantly decreased metastasis to the lungs, lymph nodes, and thoracic cavity, although no obvious effects on primary xenograft tumor growths were observed. In in vitro and in vivo experiments, the EVs incubated with the targeted antibodies were preferentially internalized by macrophages, suggesting that antibody-tagged cancer-derived EVs would be eliminated by macrophages. Our results suggested that therapeutic antibody administration effectively suppresses EV-triggered metastasis in cancer and that the removal of EVs could be a novel strategy for cancer therapy.

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“…5). Important (patho)physiological functions of EVs are increasingly recognized in different research areas including immunology (6,7), cardiovascular disorders (8), and cancer biology (9). From a clinical perspective the dynamic population of body fluid-derived EVs attracts much attention as potential biomarker and non-invasive liquid biopsy (5).…”

mentioning

confidence: 99%

Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high‐resolution flow cytometry

Kormelink

Arkesteijn

Nauwelaers³

et al. 2015

Cytometry Pt A

175

183

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Submicron-sized vesicles released by cells are increasingly recognized for their role in intercellular communication and as biomarkers of disease. Methods for highthroughput, multi-parameter analysis of such extracellular vesicles (EVs) are crucial to further investigate their diversity and function. We recently developed a highresolution flow cytometry-based method (using a modified BD Influx) for quantitative and qualitative analysis of EVs. The fact that the majority of EVs is <200 nm in size requires special attention with relation to specific conditions of the flow cytometer, as well as sample concentration and event rate. In this study, we investigated how (too) high particle concentrations affect high-resolution flow cytometry-based particle quantification and characterization. Increasing concentrations of submicron-sized particles (beads, liposomes, and EVs) were measured to identify coincidence and swarm effects, caused by the concurrent presence of multiple particles in the measuring spot. As a result, we demonstrate that analysis of highly concentrated samples resulted in an underestimation of the number of particles and an interdependent overestimation of light scattering and fluorescence signals. On the basis of this knowledge, and by varying nozzle size and sheath pressure, we developed a strategy for high-resolution flow cytometric sorting of submicron-sized particles. Using the adapted sort settings, subsets of EVs differentially labeled with two fluorescent antibodies could be sorted to high purity. Moreover, sufficient numbers of EVs could be sorted for subsequent analysis by western blotting. In conclusion, swarm effects that occur when measuring high particle concentrations severely hamper EV quantification and characterization. These effects can be easily overlooked without including proper controls (e.g., sample dilution series) or tools (e.g., oscilloscope). Providing that the event rate is well controlled, the sorting strategy we propose here indicates that high-resolution flow cytometric sorting of different EV subsets is feasible. V C 2015 International Society for Advancement of Cytometry Key terms extracellular vesicle; exosome; microvesicle; microparticle; high-resolution flow cytometry; characterization; sorting; coincidence; swarm; liposome EXTRACELLULAR vesicles (EVs) are small membrane-enclosed vesicles released by cells either by outward budding from the plasma membrane or by the fusion of multivesicular bodies with the plasma membrane resulting in the release of intracellular stored vesicles (1). The release of EVs and their content, i.e., proteins, lipids and RNAs, is tightly regulated and varies not only between different cell types but also depends on the physiological state of the producing cell (2-4). Consequently, EV release is very dynamic and the EV population is very heterogeneous. EVs can function in an autocrine or paracrine fashion, but can also enter the circulatory system and act at distant sites. Hence EVs are present in body fluids like blood, milk, urin...

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Functions and Therapeutic Roles of Exosomes in Cancer

Cited by 212 publications

References 78 publications

The Multiple Roles of Exosomes in Metastasis

The Multiple Roles of Exosomes in Metastasis

Disruption of Circulating Extracellular Vesicles as a Novel Therapeutic Strategy against Cancer Metastasis

Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high‐resolution flow cytometry

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