Abstract
Exosomes have been implicated in the cell-cell transfer of oncogenic proteins and genetic material. We speculated this may be one mechanism by which an intrinsically platinum-resistant population of epithelial ovarian cancer (EOC) cells imparts its influence on surrounding tumor cells. To explore this possibility we utilized a platinum-sensitive cell line, A2780 and exosomes derived from its resistant subclones, and an unselected, platinum-resistant EOC line, OVCAR10. A2780 cells demonstrate a ~2-fold increase in viability upon treatment with carboplatin when pre-exposed to exosomes from platinum-resistant cells as compared to controls. This coincided with increased epithelial to mesenchymal transition (EMT). DNA sequencing of EOC cell lines revealed previously unreported somatic mutations in the Mothers Against Decapentaplegic Homolog 4 (SMAD4) within platinum-resistant cells. A2780 cells engineered to exogenously express these SMAD4 mutations demonstrate up-regulation of EMT markers following carboplatin treatment, are more resistant to carboplatin, and release exosomes which impart a ~1.7-fold increase in resistance in naive A2780 recipient cells as compared to controls. These studies provide the first evidence that acquired SMAD4 mutations enhance the chemo-resistance profile of EOC and present a novel mechanism in which exchange of tumor-derived exosomes perpetuates an EMT phenotype, leading to the development of subpopulations of platinum-refractory cells.
Highlights
Ovarian cancer remains the leading cause of death of all gynecological malignancies due, in part, to a dearth of treatment options and the evolution of platinumresistant disease
While emphasis in the epithelial ovarian cancer (EOC) field is focused on tumor-stroma communication during neoplastic advancement, we report here, the first evidence of the importance of the intricate exchange of exosome-mediated crosstalk within EOC tumors leading to chemotherapeutic resistance by way of activation of epithelial to mesenchymal transition (EMT)
To examine if exosomes isolated from platinumresistant clones are taken up by the platinum-sensitive parental, population we utilized the classic A2780 (IC50 of 11 μM carboplatin) cell line and two independentlyderived carboplatin resistant clones, C30 (IC50 of 325 μM carboplatin) and CP70 (IC50 of 120 μM carboplatin) [41,42,43] (Supplementary Table 1)
Summary
Ovarian cancer remains the leading cause of death of all gynecological malignancies due, in part, to a dearth of treatment options and the evolution of platinumresistant disease. The last major advance occurred in the early 1990’s with the introduction of the mitotic inhibitor, paclitaxel, that further improved OS 3-15 months (depending on the study) when used in combination with platinum [6,7,8]. Despite these advances, tumor progression and recurrences still occur in approximately 80% of advanced stage ovarian cancer patients and result in mortality as a result of acquired resistance to platinum-based antineoplastic drugs. Platinum-resistance has been attributed to several factors including, but not limited to, increased glutathione synthesis, increased drug efflux, increased DNA damage repair, and/or increased ability to undergo epithelial to mesenchymal transition (EMT) [9,10,11,12,13,14,15]
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