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

: 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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LncRNA SPOCD1-AS from ovarian cancer extracellular vesicles remodels mesothelial cells to promote peritoneal metastasis via interacting with G3BP1

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01899-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Conghui Wang ◽

Jiaying Wang ◽

Xiameng Shen ◽

Mingyue Li ◽

Yongfang Yue ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Peritoneal Metastasis ◽

Cancer Metastasis ◽

Cancer Therapeutics ◽

Mesothelial Cells ◽

Ovarian Cancer Cells ◽

Adhesion Assay ◽

Mesenchymal Transition

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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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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Extracellular Vesicles and Ovarian Cancer

10.5772/intechopen.101412 ◽

2021 ◽

Author(s):

Diego Aviles ◽

David Warshal ◽

Lauren Krill ◽

Olga Ostrovsky

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Immune Modulation ◽

Treatment Modalities ◽

Early Screening ◽

Novel Targets ◽

Immunomodulatory Therapies ◽

Improve Clinical Outcome ◽

Screening And Diagnosis

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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Metagenomic Analysis of Serum Microbe-Derived Extracellular Vesicles and Diagnostic Models to Differentiate Ovarian Cancer and Benign Ovarian Tumor

Cancers ◽

10.3390/cancers12051309 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1309 ◽

Cited By ~ 1

Author(s):

Se Ik Kim ◽

Nayeon Kang ◽

Sangseob Leem ◽

Jinho Yang ◽

HyunA Jo ◽

...

Keyword(s):

Ovarian Cancer ◽

Extracellular Vesicles ◽

Ovarian Tumor ◽

Ovarian Tumors ◽

Metagenomic Analysis ◽

Serum Samples ◽

Benign Ovarian Tumor ◽

Diagnostic Models ◽

Test Sets ◽

Benign Ovarian Tumors

We aimed to develop a diagnostic model identifying ovarian cancer (OC) from benign ovarian tumors using metagenomic data from serum microbe-derived extracellular vesicles (EVs). We obtained serum samples from 166 patients with pathologically confirmed OC and 76 patients with benign ovarian tumors. For model construction and validation, samples were randomly divided into training and test sets in the ratio 2:1. Isolation of microbial EVs from serum samples of the patients and 16S rDNA amplicon sequencing were carried out. Metagenomic and clinicopathologic data-based OC diagnostic models were constructed in the training set and then validated in the test set. There were significant differences in the metagenomic profiles between the OC and benign ovarian tumor groups; specifically, genus Acinetobacter was significantly more abundant in the OC group. More importantly, Acinetobacter was the only common genus identified by seven different statistical analysis methods. Among the various metagenomic and clinicopathologic data-based OC diagnostic models, the model consisting of age, serum CA-125 levels, and relative abundance of Acinetobacter showed the best diagnostic performance with the area under the receiver operating characteristic curve of 0.898 and 0.846 in the training and test sets, respectively. Thus, our findings establish a metagenomic analysis of serum microbe-derived EVs as a potential tool for the diagnosis of OC.

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Chemotherapy‐induced peripheral neuropathy among patients with ovarian cancer

International Journal of Gynecology & Obstetrics ◽

10.1002/ijgo.13137 ◽

2020 ◽

Vol 149 (3) ◽

pp. 303-308 ◽

Cited By ~ 1

Author(s):

Lin Jin ◽

Yu Zhang ◽

Wenqing Yang

Keyword(s):

Ovarian Cancer ◽

Peripheral Neuropathy

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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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Phase II trial of the novel epothilone ZK-EPO in patients with platinum resistant ovarian cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.5527 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 5527-5527 ◽

Cited By ~ 8

Author(s):

G. J. Rustin ◽

N. S. Reed ◽

G. Jayson ◽

J. A. Ledermann ◽

M. Adams ◽

...

Keyword(s):

Ovarian Cancer ◽

Peripheral Neuropathy ◽

Phase Ii ◽

Phase Ii Trial ◽

Sensory Neuropathy ◽

Significant Activity ◽

Good Tolerability ◽

Efficacy Analysis ◽

Platinum Resistant ◽

Ovarian Cancer Cell Lines

5527 Background: The rationally designed, fully synthetic epothilone ZK-EPO has demonstrated significant activity against ovarian cancer cell lines. The results of the first completed phase I study (one 30-min infusion q3w) indicated good tolerability, with peripheral neuropathy as the most common toxicity; signs of activity, including objective responses, were reported. A randomised phase II trial was performed to determine the efficacy, safety and tolerability of 2 infusion durations in patients with platinum-resistant ovarian cancer. Methods: Eligible patients were at first or second relapse, had a platinum-free interval of <6 months, and disease evaluable by RECIST or, if not measurable, by CA125 (GCIG criteria). Patients were randomised to receive 3-hour or 30-min infusions of 16 mg/m2 ZK- EPO administered 3-weekly. Simon’s two-step design was used; 13–34 patients were to be accrued per arm. An arm would be continued if at least 2/13 patients responded. The drug would be considered efficacious if ≥6/34 patients responded. Results: To date, 63 patients have entered the study (accrual completed November 2006). Data is currently available on the 30 patients in step 1. Four patients were excluded from efficacy analysis due to tumor histology (clear or mucinous), as per protocol. 24 patients were taxane pre-treated. 4/13 patients responded in the 3-hour arm so accrual continued; in the 30-min arm 1/13 responded. A total of 101 infusions were administered to patients in step 1. The most common drug-related toxicity >grade 1 in the 3-hour and 30-min arm was grade 2–3 peripheral sensory neuropathy (3-hour: 9/15 patients, 30 min: 5/15 patients). Two patients withdrew because of neuropathy, both in the 3-hour arm. Other drug-related toxicities >grade 1 occurring in >1 patient were fatigue (n=3), arthralgia (n=3), nausea (n=3) and lethargy (n=2). Conclusion: Preliminary results indicate that ZK-EPO, administered as a 3-hour infusion at a dose of 16 mg/m2, has promising activity against platinum-resistant ovarian cancer. Updated response data on all patients will be presented. Peripheral neuropathy currently appears to be the only noteworthy toxicity of ZK-EPO. [Table: see text]

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