Comparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations

Abstract

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.

“DEPHENCE” system—a novel regimen of therapy that is urgently needed in the high-grade serous ovarian cancer—a focus on anti-cancer stem cell and anti-tumor microenvironment targeted therapies

“…Treatment of olaparib-resistant ovarian cancer cell line with napabucasin, the STAT3 inhibitor, improved PARPi sensitivity ( 492 ). Hypoxia and therapy-induced senescence are the key drivers of primary chemo-refractoriness and secondary chemoresistance of HGSOC ( 493 ). Hypoxic TME induces the M2-phenotype in TAMs, which, in turn, secrete exosomes containing miR-223 that, when transported into ovarian cancer cells, makes them chemoresistant ( 494 ).…”

“…Simultaneously, identification of potentially resistant tumors is of the utmost importance for successful therapy. Identification of ovarian cancer cells with high-stress signature and disturbed drug responsiveness could optimize the subsequent therapy to attenuate their function or eliminate them from the tumor ( 493 , 495 , 496 ). Moreover, as HGSOC tumors are characterized by temporal heterogeneity, the repetitive circulating tumor DNA (ctDNA)/CTCs testing should be performed to have the most actual picture of the disease.…”

Prediction of Chemoresistance—How Preclinical Data Could Help to Modify Therapeutic Strategy in High-Grade Serous Ovarian Cancer

“…One of the most important stressors originating from tumor TME is hypoxia which regulates cancer aggressiveness, invasiveness, metastatic potential, and chemoresistance through hypoxia-inducible factor-1 alpha (HIF-1α). It is speculated that hypoxia is the key driver of primary chemo-refractoriness of HGSOC [117]. In ovarian cancer samples of non-responders to chemotherapy, the down-regulation of angiogenesis-associated protein angiopoietin-like 4 (ANGPTL4), epidermal growth factor receptor HER3, and HIF-1α was observed [118].…”

“…Paclitaxel and platinum can cause changes akin to these observed in the response to TME stressors. All of them are indicators of therapy-induced senescence (TIS) and consist in autophagy, metabolic reprogramming, and EMT [117]. TIS describes a molecular and metabolic state of cancer cells that are able to escape dormancy and restore the recurrent tumor with use of acquired adaptations developed in response to the stressors, including previous chemotherapy.…”

Metronomic and single high-dose paclitaxel treatments produce distinct heterogenous chemoresistant cancer cell populations

“…High grade serous ovarian cancer (HGSOC) has the highest mortality rate among all gynecological malignancies with the majority of patients experiencing resistance to chemotherapies, including the frontline chemotherapeutic, paclitaxel (PTX) 1 . PTX is an anti-mitotic agent that binds to β-tubulin stabilizing microtubules (MTs) and prevents their disassembly, thus inhibiting mitosis and eventually triggering apoptosis.…”