Anjali Bhatt

Introduction. Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer due to lack of early clinical symptoms, diagnostic markers, and chemoresistance.¹ The exact cause of EOC is unknown, but it is multifactorial with genetic, environmental, and socioeconomic factors.² In terms of clinical presentation, a patient with EOC typically presents with non-specific symptoms and because of this, patients are usually at an advanced stage at time of diagnosis.¹ Diagnosis is made with transvaginal ultrasound, CT or MRI of pelvis, pathological diagnosis, and increased levels of CA-125. Treatment includes debulking cytoreductive surgery followed by platinum-based chemotherapy. However, disease recurrence is often observed in patients with platinum-resistant ovarian cancer. Recent research has indicated the role of the tumor microenvironment (TME) in tumor progression. Exosomes are thought to be vital in the reciprocal intercellular communication between EOC cells and cells in the TME, especially tumor-associated macrophages (TAMs), by carrying cargo such as lipids, proteins, and nucleic acids.³ The mechanisms by which exosomes mediate crosstalk between EOC cells and M2 macrophages to contribute to chemoresistance are unknown. Methods. The first step in detailing these mechanisms was treating unpolarized macrophages with EOC cell-derived exosomes and performing western blots on the macrophages.¹ miRNA microarrays were performed to determine upregulation of specific miRNAs in exosomes derived from EOC cells and TAMs.¹ Then, western blots were conducted to observe increased or decreased protein levels in the TAMs after transfection with exosomes.¹ Next, exosomes released from M2 macrophages were analyzed in relation to pro-tumor phenotypes.⁴ This was done by utilizing luciferase reporter assays and western blots to determine the downstream targets of exosomal miRNAs.⁴ Parameters such as apoptosis rates, number of cell colonies, and chemoresistance were measured.⁴  Results. Results indicate that macrophages were polarized to an M2 phenotype when transfected with exosomes released from EOC cells.¹ These exosomes contained upregulated miR-21-3p, miR-125-5p, and miR-181d-5p, which were responsible for producing decreased SOCS 4/5 levels and increased p-STAT3 in macrophages, and these changes were linked to being responsible for M2 polarization.¹ Macrophage-derived exosomes contained upregulated miR-223.⁴ When EOC cells were treated with miR-223, apoptosis rates decreased, there was an increased number of cell colonies, and increased chemoresistance through miR-223 targeting of PTEN.⁴  Conclusion: The significance of this data lies in the ability to discover potential biomarkers to aid in predicting how a patient may respond to chemotherapy and to develop more targeted therapeutics.⁵

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