Abstract
Exosomes are cell-secreted microvesicles that play important roles in epithelial ovarian cancer (EOC) progression, as they are constantly secreted into ascites fluids. While cells spontaneously release exosomes, alterations in intracellular calcium or extracellular pH can release additional exosomes. Yet, little is known about how these exosomes compare to those that are continuously released without stimulation and how they mediate cellular activities important in cancer progression. Here, we demonstrate that chelation of extracellular calcium leads to release of chelation-induced exosomes (CI-exosomes) from OVCAR-3 EOC cells. CI-exosomes display a unique miRNA profile compared to naturally secreted exosomes (SEC-exosomes). Furthermore, treatment with CI- and SEC-exosomes leads to differential biophysical and functional changes including, adhesion and migration in EOC-derived fibroblasts that suggest the development of a malignant tumor microenvironment. This result highlights how tumor environmental factors contribute to heterogeneity in exosome populations and how different exosome populations mediate diversity in stromal cell behavior.
Highlights
Serous epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy with 5-year relative survival rate of 45%1
EOC cells are shed from the primary tumor into the peritoneum as individual cells or multi-cellular spheroids and often adhere and metastasize to the omentum, a common site for EOC metastasis[2]
Exosomes shed from the primary tumor into the ascites fluid may play an important role in preparing this niche for EOC metastasis[60]
Summary
Serous epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy with 5-year relative survival rate of 45%1. Carcinoma associated fibroblasts (CAFs) are a major contributor to these malignant tumor stromas[5] They mediate hallmark cancer cell behaviors by secreting paracrine factors to alter growth and survival, extracellular matrix (ECM) proteins for matrix remodeling, and pro-inflammatory signals important in tumors and tissues[6]. Exosome exchange influences cancer-related pathways at all levels, from the initial stages of tumorigenesis to acquisition of drug resistance, and in critical processes that mediate tumor metastasis. These nanovesicles guide critical proteins, transcription factors, and miRNAs through complex extracellular environments to impact distant cell signaling pathways important in cancer dissemination[10]. It is pivotal to investigate the unique population of exosomes that are released upon extracellular calcium chelation
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