Role of exosomal miRNA's relased from cancer stem cells in ovarian cancer growth and progression

Despite the recent advancements in the treatment of OC, it remains the seventh most common cancer in women worldwide. Cancer stem cells (CSCs) are a unique cell population described by their ability to indefinitely self-renew, proliferate, initiate, and propagate. Evidence suggests that the interaction between cancer stem cells with their microenvironment play a critical role in cancer progression. Exosomes which are the key players of the microenvironment are nano-sized (50-180nm) endosomal pathway-derived vesicles that present in almost all biological fluids. Transporting information via exosomes and exosomal miRNAs is deemed to be the crucial way of intercellular communication that is as essential as the cell-to-cell contact-dependent signaling. As a key regulator of cellular signaling, both normal, and cancer stem cells secrete exosomes to orchestrate diverse autocrine and paracrine functions which alter tumor micro‐environment, growth, progression, and putative immunological function. There is still not much known about how ovarian cancer stem cells (OCSCs) interact with their tumor microenvironment to promote oncogenic phenotype. Thus, in this study, we investigate whether the OCSCs-derived exosomal miRNAs mirror and orchestrate that of the tumor microenvironment and thus could be used diagnostically in ovarian cancer patients. To this end, we evaluated significantly differentially expressed miRNAs between OCSCs exosomes and their cells of origin using the Affymetrix Gene Chip miRNA 4.0 microarrays. Several miRNAs were found to be significantly upregulated in both OCSCs and their exosomes. In addition we found many common up/down regulated miRNAs (miR-103a-3p, miR-20a-5p,miR-125b-5p, miR-17-5p, miR-27a-3p, miR-8075, miR-4487) with the microarray data in which tumor-associated macrophage (TAM) exosomes and their cells of origin were compared. We also found that OCSCs secrete exosomes enriched in miR-103a-3p, which has been shown in our work to increases cancer migration, invasion and angiogenesis as well as proliferation and induces polarization of M0 type macrophages toward immunosuppressive M2-type macrophages. We were validated this in vitro effect of the miR-103a-3p in ovarian cancer orthotopic mouse model by using nanoliposomal-miR-103a-3p and investigating the role of these miRs in OC cells and CSCs proliferation, migration, invasion and tumor growth. Overall, our data suggest that OCSCs and OCSCs secreted exosomes may contribute tumor microenvironment especially by regulating TAMs by transferring oncogenic miRs and using them as a progression and invasion tools within tumor microenvironment.