Peritoneal dissemination is a distinct form of metastasis in ovarian cancer that precedes hematogenic or lymphatic metastasis. Exosomes are extracellular vesicles of 30–150 nm in diameter secreted by different cell types and internalized by target cells. There is emerging evidence that exosomes facilitate the peritoneal dissemination of ovarian cancer by mediating intercellular communication between cancer cells and the tumor microenvironment through the transfer of nucleic acids, proteins, and lipids. Furthermore, therapeutic applications of exosomes as drug cargo delivery are attracting research interest because exosomes are stabilized in circulation. This review highlights the functions of exosomes in each process of the peritoneal dissemination of ovarian cancer and discusses their potential for cancer therapeutics.

Exosomes are extracellular vesicles involved in several biological and pathological molecules and can carry many bioactive materials to target cells. They work as important mediators of cell-cell communication and play essential roles in many diseases, especially in cancer. Ovarian cancer is one of the most common gynecological malignancies. Most patients are diagnosed at advanced stages involving widespread peritoneal dissemination, resulting in poor prognosis. Emerging evidence has shown that exosomes play vital roles throughout the progression of ovarian cancer. Moreover, the development of engineered exosome-based therapeutic applications— including drug delivery systems, biomolecular targets and immune therapy—has increased drastically. Herein, we review the functional features of exosomes in ovarian cancer progression and the therapeutic application potential of exosomes as novel cancer treatments.

Although bevacizumab (BEV) plays a key role in ovarian cancer treatment, BEV resistance is often observed in clinical settings. This study aimed to identify the genes responsible for BEV resistance. C57BL/6 mice inoculated with ID-8 murine ovarian cancer cells were treated with anti-VEGFA antibody or IgG (control) twice weekly for 4 weeks. The mice were sacrificed, then, RNA was extracted from the disseminated tumors. qRT-PCR assays were performed to identify angiogenesis-related genes and miRNAs that were altered by anti-VEGFA treatment. SERPINE1/PAI-1 was found to be upregulated during BEV treatment. Therefore, we focused on miRNAs to elucidate the mechanism underlying the upregulation of PAI-1 during BEV treatment. Kaplan–Meier plotter analysis revealed that higher expression levels of SERPINE1/PAI-1 were associated with poor prognoses among BEV-treated patients, suggesting that SERPINE1/PAI may be involved in the acquisition of BEV resistance. miRNA microarray analysis followed by in silico and functional assays revealed that miR-143-3p targeted SERPINE1 and negatively regulated PAI-1 expression. The transfection of miR-143-3p suppressed PAI-1 secretion from ovarian cancer cells and inhibited in vitro angiogenesis in HUVECs. Next, miR-143-3p-overexpressing ES2 cells were intraperitoneally injected into BALB/c nude mice. ES2-miR-143-3p cells downregulated PAI-1 production, attenuated angiogenesis, and significantly inhibited intraperitoneal tumor growth following treatment with anti-VEGFA antibody. Continuous anti-VEGFA treatment downregulated miR-143-3p expression, which upregulated PAI-1 and activated an alternative angiogenic pathway in ovarian cancer. In conclusion, the substitution of this miRNA during BEV treatment may help overcome BEV resistance, and this may be used as a novel treatment strategy in clinical settings. Implications: Continuous administration of VEGFA antibody upregulates SERPINE1/PAI-1 expression via the downregulation of miR-143-3p, which contributes to acquiring bevacizumab resistance in ovarian cancer.

RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC.

Ovarian clear-cell carcinoma (OCCC), particularly advanced or recurrent settings, is generally resistant to platinum-based chemotherapy, warranting novel therapeutic strategies. Mutations in the PI3K/AKT/mTOR pathway are frequently reported in OCCC. Therefore, we hypothesized that the PI3K/mTOR dual inhibitor, GSK458, and arsenic trioxide (As2O3) may exert synergistic antitumor effects on OCCC. We investigated the effects of GSK458, As2O3, and the combination of GSK458 and As2O3 on cell viability, colony formation, and apoptosis in seven OCCC cells. Mechanistically, transcriptomic differences were assessed among the groups. Additionally, their antitumor effects were evaluated on the three-dimensional cultures of OCCC patient-derived xenografts as well as in vivo. Low-dose combination of GSK458 and As2O3 exerted synergistic antitumor effects in vitro. Viability of the three-dimensional OCCC patient-derived xenograft cultures treated with the combination of GSK458 and As2O3 decreased to 23.8% of that of the control. RNA sequencing revealed that the mechanism was associated with cell cycle and DNA damage repair. The combination of GSK458 and As2O3 synergistically inhibited the PI3K/AKT/mTOR pathway and angiogenesis and increased apoptosis. Compared with any monotherapy, the combination treatment significantly suppressed tumor growth in vivo, thereby enhancing survival. Overall, our findings highlight the potential of the novel combination of GSK458 and As2O3 for OCCC treatment.

High-grade serous carcinoma (HGSC) is the most common ovarian cancer subtype, typically diagnosed at late stages with poor prognosis. Understanding early molecular events driving HGSC progression is crucial for timely detection and development of effective treatment strategies. We performed and integrated spatial cell-type resolved proteomics and paired transcriptomics across 25 women with precursor lesions of the fallopian tube and/or HGSC. Epithelial cell signatures revealed early activation of SUMOylation machinery, increased ATR and Wnt signaling, and enhanced MHC-I antigen presentation along the disease trajectory. The stroma exhibited extracellular matrix remodeling and interferon-mediated inflammation. Serous tubal intraepithelial carcinomas (STICs) in cancer patients contained a pro-coagulative signature and reduced APOA1/2 compared to STICs in individuals without cancer. We functionally established important roles of epithelial-derived TRIP13 and SUMOylation, and cancer-associated fibroblast-derived SULF1 and BGN in HGSC progression. These findings provide unique molecular insights into HGSC pathogenesis and identify potential new therapeutic targets for intervention.