Extracellular Vesicles and Ovarian Cancer

Extracellular vesicles (EVs) are a varied group of cell-derived, microscopic, fluid-filled pouches released from cells into neighboring microenvironments that are quickly gaining recognition as a potentially powerful tool against epithelial ovarian cancer (EOC). Recent studies show that not only do EVs play an integral part in the development of cancer through intercellular communication, cell survival, and immune modulation but also may assist with early diagnosis and improved treatments. EOC currently has few effective screening options for early detection of this disease; and, therefore, it is detected at an advanced stage where it is more likely to recur, develop chemoresistance, and ultimately become fatal. Newer research has evaluated EVs as biomarkers for early screening and diagnosis and as novel targets for treatment of EOC. Moreover, EVs are possible targets for novel immunomodulatory therapies to directly target cancer cells or make cancer cells more susceptible to other treatment modalities. Therefore, EVs present an exciting, promising approach which may improve clinical outcome for EOC patients.

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Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

Journal of Clinical Medicine ◽

10.3390/jcm9041185 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1185 ◽

Cited By ~ 3

Author(s):

Martha Baydoun ◽

Olivier Moralès ◽

Céline Frochot ◽

Colombeau Ludovic ◽

Bertrand Leroux ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

Photodynamic Therapy ◽

Cancer Cells ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Immune Cells ◽

Surgical Techniques ◽

Ovarian Cancer Cells ◽

The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

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microRNA-141-3p-containing small extracellular vesicles derived from epithelial ovarian cancer cells promote endothelial cell angiogenesis through activating the JAK/STAT3 and NF-κB signaling pathways

Journal of Cell Communication and Signaling ◽

10.1007/s12079-020-00548-5 ◽

2020 ◽

Vol 14 (2) ◽

pp. 233-244 ◽

Cited By ~ 11

Author(s):

Sajjad Masoumi-Dehghi ◽

Sadegh Babashah ◽

Majid Sadeghizadeh

Keyword(s):

Ovarian Cancer ◽

Endothelial Cell ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Extracellular Vesicles ◽

Ovarian Cancer Cells

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Role of tissue-factor bearing extracellular vesicles released from ovarian cancer cells in platelet aggregation in vitro and venous thrombosis in mice

Thrombosis Update ◽

10.1016/j.tru.2020.100020 ◽

2021 ◽

Vol 2 ◽

pp. 100020

Author(s):

Tomoyuki Sasano ◽

Min Soon Cho ◽

Cristian Rodriguez-Aguayo ◽

Emine Bayraktar ◽

Mana Taki ◽

...

Keyword(s):

Ovarian Cancer ◽

Platelet Aggregation ◽

Venous Thrombosis ◽

Cancer Cells ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Ovarian Cancer 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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The Role and Clinical Interest of Extracellular Vesicles in Pregnancy and Ovarian Cancer

Biomedicines ◽

10.3390/biomedicines9091257 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1257

Author(s):

Nazanin Yeganeh Kazemi ◽

Benoìt Gendrot ◽

Ekaterine Berishvili ◽

Svetomir N. Markovic ◽

Marie Cohen

Keyword(s):

Ovarian Cancer ◽

Immune System ◽

Extracellular Vesicles ◽

Vascular Remodeling ◽

Immune Modulation ◽

Cancer Metastasis ◽

Cell Communication ◽

Host Immune System ◽

In Pregnancy

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.

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Phagocytosis of Extracellular Vesicles Extruded From the Placenta by Ovarian Cancer Cells Inhibits Growth of the Cancer Cells

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000001140 ◽

2018 ◽

Vol 28 (3) ◽

pp. 545-552 ◽

Cited By ~ 1

Author(s):

Qi Chen ◽

Victoria Rutten ◽

Wei-Tzu Cheng ◽

Mancy Tong ◽

Jia Wei ◽

...

Keyword(s):

Cell Cycle ◽

Ovarian Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Extracellular Vesicles ◽

Protective Factor ◽

Gynecological Cancer ◽

First Trimester ◽

Ovarian Cancer Cells ◽

Inhibition Of Proliferation

ObjectiveOvarian cancer is a common gynecological cancer, and parity is negatively associated with the incidence of this disease. This negative association is hypothesized to be due in part to shifting the balance of estrogen and progesterone toward more progesterone and reduced ovulation during pregnancy. However, studies suggested that parity is also associated with estrogen-independent gynecological cancers suggesting balance of hormones may not be the only protective factor. Extracellular vesicles (EVs) play an important role in cell-to-cell communication in physiological and pathological conditions. During pregnancy, large amounts of EVs are extruded from the placenta, and they seem to be involved in the remarkable adaptation of a woman's body to normal pregnancy. We hypothesized that EVs extruded from the placenta play a role in this protective effect.MethodsPlacental EVs were collected from first-trimester placentae, and cancer cell EVs were isolated from ovarian cancer cells. The EVs were exposed to ovarian cancer cells for 48 hours. The proliferation of cancer cells and the cell cycle were measured. In addition, phagocytosis of deported placental EVs by cancer cells was also measured.ResultsThe proliferation of cancer cells was significantly reduced by treatment with placental EVs (P = 0.001, analysis of variance), but not EVs from monocytes (P = 0.195), compared with untreated cancer cells. Furthermore, placental EVs also prevented the proliferation of cancer cells induced by cancer cell–derived EVs (P = 0.001). This inhibition of proliferation of ovarian cancer cells was partially due to phagocytosis of placental EVs by cancer cells. Phagocytosis of placental EVs delayed progression through the cell cycle. Calreticulin, a phagocytic “eat me” signal carried by placental EVs significantly inhibited ovarian cancer growth (P = 0.001).ConclusionsOur data demonstrated that EVs extruded from the placenta prevented ovarian cancer cell growth by a mechanism that involved delaying progression of the cell cycle after phagocytosis of the EVs.

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High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors

Thrombosis and Haemostasis ◽

10.1160/th15-03-0213 ◽

2016 ◽

Vol 115 (02) ◽

pp. 299-310 ◽

Cited By ~ 25

Author(s):

Shin Ito ◽

Yusuke Yoshioka ◽

Tomohiko Kanayama ◽

Yoshiyasu Nakamura ◽

Mitsuyo Yoshihara ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Surface ◽

Cancer Cells ◽

Cancer Patients ◽

Tissue Factor ◽

Extracellular Vesicles ◽

Actin Binding ◽

Ovarian Cancer Cells ◽

Filamin A ◽

Protease Activated Receptors

SummaryThromboembolic events occur frequently in ovarian cancer patients. Tissue factor (TF) is often overexpressed in tumours, including ovarian clear-cell carcinoma (CCC), a subtype with a generally poor prognosis. TF-coagulation factor VII (fVII) complexes on the cell surface activate downstream coagulation mechanisms. Moreover, cancer cells secrete extracellular vesicles (EVs), which act as vehicles for TF. We therefore examined the characteristics of EVs produced by ovarian cancer cells of various histological subtypes. CCC cells secreted high levels of TF within EVs, while the high-TF expressing breast cancer cell line MDA-MB-231 shed fewer TF-positive EVs. We also found that CCC tumours with hypoxic tissue areas synthesised TF and fVII in vivo, rendering the blood of xenograft mice bearing these tumours hypercoagulable compared with mice bearing MDA-MB-231 tumours. Incorporation of TF into EVs and secretion of EVs from CCC cells exposed to hypoxia were both dependent on the actin-binding protein, filamin-A (filA). Furthermore, production of these EVs was dependent on different protease-activated receptors (PARs) on the cell surface. These results show that CCC cells could produce large numbers of TF-positive EVs dependent upon filA and PARs. This phenomenon may be the mechanism underlying the increased incidence of venous thromboembolism in ovarian cancer patients.Supplementary Material to this article is available online at www.thrombosis-online.com.

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