BackgroundCirculating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood.MethodsTo investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments.FindingsSubstantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages.InterpretationOur results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian tissue compared to ovarian cancer patient samples and correlated with better overall survival in high-grade serous ovarian cancer patients. miR-6126 acted as a tumor suppressor by directly targeting integrin β1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin β1 mRNA levels in the exosome. Functional analysis showed that treatment of endothelial cells with miR-6126 mimic significantly reduced tube formation as well as invasion and migration capacities of ovarian cancer cells in vitro. Administration of miR-6126 mimic in an orthotopic mouse model of ovarian cancer elicited a relative reduction in tumor growth, proliferating cells and microvessel density. miR-6126 inhibition promoted oncogenic behavior by leading ovarian cancer cells to release more exosomes. Our findings provide new insights into the role of exosomal miRNA-mediated tumor progression and suggest a new therapeutic approach to disrupt oncogenic phenotypes in tumors.

Cancer is one of the major causes of mortality worldwide and advanced techniques for therapy are urgently needed. The development of novel nanomaterials and nanocarriers has allowed a major drive to improve drug delivery in cancer. The major aim of most nanocarrier applications has been to protect the drug from rapid degradation after systemic delivery and allowing it to reach tumor site at therapeutic concentrations, meanwhile avoiding drug delivery to normal sites as much as possible to reduce adverse effects. These nanocarriers are formulated to deliver drugs either by passive targeting, taking advantage of leaky tumor vasculature or by active targeting using ligands that increase tumoral uptake potentially resulting in enhanced antitumor efficacy, thus achieving a net improvement in therapeutic index. The rational design of nanoparticles plays a critical role since structural and physical characteristics, such as size, charge, shape, and surface characteristics determine the biodistribution, pharmacokinetics, internalization and safety of the drugs. In this review, we focus on several novel and improved strategies in nanocarrier design for cancer therapy.

Purpose RNA interference has the potential to specifically knock down the expression of target genes, and thereby transform cancer therapy. However, lack of effective delivery of small inhibitory RNA (siRNA) has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with nanotherapeutics, that directs effective delivery and sustained release of siRNA in tumor tissues. In this study, we evaluated therapeutic efficacy of MSV-loaded EphA2 siRNA (MSV/EphA2) with murine orthotopic models of metastatic ovarian cancers as a first step towards development of a new class of nanotherapeutics for the treatment of ovarian cancer. Experimental design Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed after i.v. administration of MSV/siRNA. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated. Results Treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for 6 weeks resulted in dose-dependent (5, 10 and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Conclusion These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer.