The influence of secreted factors and extracellular vesicles in ovarian cancer metastasis

Abstract Background Metastasis is the key cause of death in ovarian cancer patients. To figure out the biological nature of cancer metastasis is essential for developing effective targeted therapy. Here we investigate how long non-coding RNA (lncRNA) SPOCD1-AS from ovarian cancer extracellular vesicles (EVs) remodel mesothelial cells through a mesothelial-to-mesenchymal transition (MMT) manner and facilitate peritoneal metastasis. Methods EVs purified from ovarian cancer cells and ascites of patients were applied to mesothelial cells. The MMT process of mesothelial cells was assessed by morphology observation, western blot analysis, migration assay and adhesion assay. Altered lncRNAs of EV-treated mesothelial cells were screened by RNA sequencing and identified by qRT-PCR. SPOCD1-AS was overexpressed or silenced by overexpression lentivirus or shRNA, respectively. RNA pull-down and RNA immunoprecipitation assays were conducted to reveal the mechanism by which SPOCD1-AS remodeled mesothelial cells. Interfering peptides were synthesized and applied. Ovarian cancer orthotopic implantation mouse model was established in vivo. Results We found that ovarian cancer-secreted EVs could be taken into recipient mesothelial cells, induce the MMT phenotype and enhance cancer cell adhesion to mesothelial cells. Furthermore, SPOCD1-AS embedded in ovarian cancer-secreted EVs was transmitted to mesothelial cells to induce the MMT process and facilitate peritoneal colonization in vitro and in vivo. SPOCD1-AS induced the MMT process of mesothelial cells via interacting with G3BP1 protein. Additionally, G3BP1 interfering peptide based on the F380/F382 residues was able to block SPOCD1-AS/G3BP1 interaction, inhibit the MMT phenotype of mesothelial cells, and diminish peritoneal metastasis in vivo. Conclusions Our findings elucidate the mechanism associated with EVs and their cargos in ovarian cancer peritoneal metastasis and may provide a potential approach for metastatic ovarian cancer therapeutics.

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Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity?

Cells ◽

10.3390/cells10082117 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2117

Author(s):

Gabriele Storti ◽

Maria Giovanna Scioli ◽

Bong-Sung Kim ◽

Sonia Terriaca ◽

Elena Fiorelli ◽

...

Keyword(s):

Ovarian Cancer ◽

Adipose Tissue ◽

Tumor Progression ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Cancer Metastasis ◽

Ovarian Cancer Cells ◽

Cancer Therapies ◽

Therapeutic Opportunity

Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.

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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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The emerging roles of extracellular vesicles in ovarian cancer

Current Drug Metabolism ◽

10.2174/1389200221666201110155721 ◽

2020 ◽

Vol 21 ◽

Author(s):

Yin-xue Wang ◽

Yi-xiang Wang ◽

Yi-ke Li ◽

Shi-yan Tu ◽

Yi-qing Wang

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Large Scale ◽

Current Treatment ◽

Detection Methods ◽

Drug Resistant ◽

Apoptotic Bodies ◽

Biological Mechanisms ◽

Gynecological Malignancy ◽

Resistance To Chemotherapy

: Ovarian cancer (OC) is one of the deadliest gynecological malignancy. Epithelial ovarian cancer (EOC) is its most common form. OC has both a poor prognosis and a high mortality rate due to the difficulties of early diagnosis, the limitation of current treatment and resistance to chemotherapy. Extracellular vesicles is a heterogeneous group of cellderived submicron vesicles which can be detected in body fluids, and it can be classified into three main types including exosomes, micro-vesicles, and apoptotic bodies. Cancer cells can produce more EVs than healthy cells. Moreover, the contents of these EVs have been found distinct from each other. It has been considered that EVs shedding from tumor cells may be implicated in clinical applications. Such as a tool for tumor diagnosis, prognosis and potential treatment of certain cancers. In this review, we provide a brief description of EVs in diagnosis, prognosis, treatment, drug-resistant of OC. Cancer-related EVs show powerful influences on tumors by various biological mechanisms. However, the contents mentioned above remain in the laboratory stage and there is a lack of large-scale clinical trials, and the maturity of the purification and detection methods is a constraint. In addition, amplification of oncogenes on ecDNA is remarkably prevalent in cancer, it may be possible that ecDNA can be encapsulated in EVs and thus detected by us. In summary, much more research on EVs needs to be perform to reveal breakthroughs in OC and to accelerate the process of its application on clinic.

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Extracellular vesicles derived from ascitic fluid enhance growth and migration of ovarian cancer cells

Scientific Reports ◽

10.1038/s41598-021-88163-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Aparna Mitra ◽

Kyoko Yoshida-Court ◽

Travis N. Solley ◽

Megan Mikkelson ◽

Chi Lam Au Yeung ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Carcinoma ◽

Advanced Stages ◽

And Migration ◽

Cancer Spheroids ◽

Omental Fat ◽

Low Expression

AbstractOvarian cancer is associated with a high mortality rate due to diagnosis at advanced stages. Dissemination often occurs intraperitoneally within the ascites fluid. The microenvironment can support dissemination through several mechanisms. One potential ascites factor which may mediate dissemination are EVs or extracellular vesicles that can carry information in the form of miRNAs, proteins, lipids, and act as mediators of cellular communication. We present our observations on EVs isolated from ascitic supernatants from patients diagnosed with high grade serous ovarian carcinoma in augmenting motility, growth, and migration towards omental fat. MicroRNA profiling of EVs from malignant ascitic supernatant demonstrates high expression of miR 200c-3p, miR18a-5p, miR1246, and miR1290 and low expression of miR 100- 5p as compared to EVs isolated from benign ascitic supernatant. The migration of ovarian cancer spheroids towards omental fat is enhanced in the presence of malignant ascitic EVs. Gene expression of these cells showed increased expression of ZBED2, ZBTB20, ABCC3, UHMK1, and low expression of Transgelin and MARCKS. We present evidence that ovarian ascitic EVs increase the growth of ovarian cancer spheroids through miRNAs.

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Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer

Nature Communications ◽

10.1038/ncomms14470 ◽

2017 ◽

Vol 8 (1) ◽

Cited By ~ 104

Author(s):

Akira Yokoi ◽

Yusuke Yoshioka ◽

Yusuke Yamamoto ◽

Mitsuya Ishikawa ◽

Shun-ichi Ikeda ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Peritoneal Dissemination

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Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer

Journal of Extracellular Vesicles ◽

10.1002/jev2.12073 ◽

2021 ◽

Vol 10 (5) ◽

Author(s):

Yi Zhang ◽

Chao Li ◽

Yi Qin ◽

Pasquale Cepparulo ◽

Michael Millman ◽

...

Keyword(s):

Ovarian Cancer ◽

Peripheral Neuropathy ◽

Extracellular Vesicles

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CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

Cancer Growth and Metastasis ◽

10.1177/1179064418767882 ◽

2018 ◽

Vol 11 ◽

pp. 117906441876788 ◽

Cited By ~ 16

Author(s):

Lynn Roy ◽

Alexander Bobbs ◽

Rachel Sattler ◽

Jeffrey L Kurkewich ◽

Paige B Dausinas ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Metastasis ◽

Ex Vivo ◽

Surface Protein ◽

Ovarian Cancer Cells ◽

Metastatic Niche ◽

Attractive Therapeutic Target ◽

Peritoneal Mesothelium

Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.

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