Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations

Simple Summary Epithelial ovarian cancer (EOC) is a gynecological disease that is complicated to treat due to its heterogenous nature and because many women develop resistance to various therapeutic strategies. Tumor recurrence can be examined as a two-pronged approach: resistance developed after multiple exposures to frontline anticancer drugs or resistance developed in response to poor microenvironmental conditions, such as hypoxia. Although there are numerous ways to confer chemoresistance, studies have shown that chemoresistant EOC cells release unique secretome profiles that include cytokines, growth factors, and extracellular vesicles (EVs). These secreted factors activate intracellular pathways that contribute to chemoresistance. Secreted EVs transfer biomaterials (including proteins, RNAs, and microRNAs) to other cells, which is critical in cell-cell communication; thus, changes in EV content, in particular exosome miRNAs, have been used to project EOC prognosis. This review examines the feedback loop where chemoresistant EOC cells release unique secretome profiles that confer chemoresistance in normal bystander cells and cancer cells. High-grade serous ovarian cancer (HGSOC) constitutes the majority of all ovarian cancer cases and has staggering rates of both refractory and recurrent disease. While most patients respond to the initial treatment with paclitaxel and platinum-based drugs, up to 25% do not, and of the remaining that do, 75% experience disease recurrence within the subsequent two years. Intrinsic resistance in refractory cases is driven by environmental stressors like tumor hypoxia which alter the tumor microenvironment to promote cancer progression and resistance to anticancer drugs. Recurrent disease describes the acquisition of chemoresistance whereby cancer cells survive the initial exposure to chemotherapy and develop adaptations to enhance their chances of surviving subsequent treatments. Of the environmental stressors cancer cells endure, exposure to hypoxia has been identified as a potent trigger and priming agent for the development of chemoresistance. Both in the presence of the stress of hypoxia or the therapeutic stress of chemotherapy, cancer cells manage to cope and develop adaptations which prime populations to survive in future stress. One adaptation is the modification in the secretome. Chemoresistance is associated with translational reprogramming for increased protein synthesis, ribosome biogenesis, and vesicle trafficking. This leads to increased production of soluble proteins and extracellular vesicles (EVs) involved in autocrine and paracrine signaling processes. Numerous studies have demonstrated that these factors are largely altered between the secretomes of chemosensitive and chemoresistant patients. Such factors include cytokines, growth factors, EVs, and EV-encapsulated microRNAs (miRNAs), which serve to induce invasive molecular, biophysical, and chemoresistant phenotypes in neighboring normal and cancer cells. This review examines the modifications in the secretome of distinct chemoresistant ovarian cancer cell populations and specific secreted factors, which may serve as candidate biomarkers for aggressive and chemoresistant cancers.