Epithelial ovarian cancer (EOC) patients frequently suffer from thrombocytosis, which leads to a poor prognosis. However, the mechanism underlying platelet regulation of biological behavior in EOC remains unclear. The associations between clinicopathological characteristics and thrombocytosis in 171 EOC patients were studied, preoperative thrombocytosis was significantly associated with the stage, metastasis scope, level of preoperative CA125 and overall survival. When SKOV3 cells were cocultured with platelet microparticles (PMPs), the expression of molecules associated with epithelial-mesenchymal transition (EMT) was increased. The proliferation and migration of SKOV3 cells were also enhanced. Based on the miRNA microarray of the PMPs derived between thrombin-stimulating and apoptotic platelets, we demonstrated that over-expression or complete knockdown of miR-939 in the SKOV3 cells strengthened or weakened EMT. Secretory phospholipase A2 type IIA (sPLA2-IIa) has been shown to mediate PMPs intake by SKOV3 cells. The knockdown of sPLA2-IIa in SKOV3 cells verified that PMPs were involved in crosstalk during the regulation of cancer cells by transferring miRNA. This study revealed an important role for PMPs in the crosstalk of platelets and cancer cells through miR-939 shedding mediated by sPLA2-IIa, which enables EOC to undergo EMT and enhances cancer progression. Our findings pave the way for developing a novel therapeutic strategy for EOC targets such as PMPs, miR-939 or sPLA2-IIa.

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Abstract. Ovarian cancer (OC), of which epithelial ovarian cancer (EOC) is the most common, is the deadliest gynecological tumor because of the difficulties in detection at early stages, and metastasis and chemoresistance at advanced stages. Tumor-associated macrophages (TAMs) differentiate through alternative pathways and play important roles in tumor growth and metastasis. However, the underlying mechanism remains unclear. Here, we established a mouse TAM model using bone marrow monocytes and conditioned medium (CM) of TAMs to culture ID8 mouse EOC cells. The results showed that TAM CM accelerated the proliferation and migration of ID8 cells. In a previous study, gene chip analysis showed that human TAMs expressed significantly higher levels of insulinlike growth factor-1 (IGF1) than undifferentiated M0 myeloid cells. In the present study, we observed that the IGF1 level was higher in human EOC specimens than that in benign ovarian tumor specimens, and further analysis showed that a higher level of IGF1 was related to more advanced clinical stage and liver metastasis. Therefore, we hypothesized that TAMs may accelerate the proliferation and migration of EOC cells by upregulating IGF1. As expected, increased IGF1 expression at both the mRNA and protein levels was observed in ID8 cells cultured with TAM CM, whereas blockade of the IGF1 pathway in ID8 cells with an IGF1 neutralizing antibody effectively reversed the promotion of proliferation and migration. Finally, we inhibited the phosphorylation of insulin-like growth factor-1 receptor (IGF1R) and its downstream molecules Akt and Erk with the IGF1R inhibitor linsitinib, and observed that the treatment effectively suppressed the proliferation and migration of ID8 cells exposed to TAM CM. Thus, we demonstrated that TAMs may promote the growth and metastasis of EOC via the activation of the IGF1 pathway; thus, targeting the IGF1 pathway may be promising for EOC therapy.

Purpose Epithelial ovarian cancer (EOC) is one of the most malignant cancers in the gynecologic system. Many patients are diagnosed at an advanced stage with disseminated intra-peritoneal metastases. EOC spreads via both direct extension and transcoelomic spread. However, the interplay between human peritoneal mesothelial cells (HPMCs) and EOC cells is still ambiguous. We hypothesize that integrins (ITG) in HPMCs may play important roles in EOC metastasis. Methods The expression of different integrin subtypes from HPMCs was assessed using Western blotting. The expression of integrin α5β1 (ITGA5B1) and its co-localization with asparaginyl endopeptidase (AEP) in HPMCs derived from EOC patients (EOC-HPMCs) were assessed using immunofluorescence. The role and mechanism of the exosomal ITGA5B1/AEP complex in HPMCs was assessed using both in vitro and in vivo assays. A retrospective study involving 234 cases was carried out to assess ITGA5B1 and AEP levels in circulating sera and ascites of EOC patients, as well as associations between ITGA5B1/AEP expression and overall survival. Results We found that ITGA5B1was highly expressed and co-localized with AEP in EOC cells, and that the exosomal ITGA5B1/AEP complex secreted by EOC cells played an important role in the proliferation and migration of HPMCs. High levels of exosomal ITGA5B1/AEP were also found in circulating sera and ascites of EOC patients, and the expression of ITGA5B1/AEP in EOC tissues was found to be negatively associated with overall survival. Conclusions Our data indicate that EOCs may regulate the function of HPMCs through exosomal ITGA5B1/AEP, which may be crucial for peritoneal metastasis.

In contrast to other solid tumors within the abdominal cavity, epithelial ovarian cancers (EOCs) tend to undergo peritoneal metastasis. Thus, the peritoneal immune microenvironment is crucial for EOC progression. Previous reports indicate that the main immune cells within the peritoneum are M2 macrophages, specifically tumor‐associated macrophages (TAMs). The communication between TAMs and tumor cells plays an important role in EOC development, and exosomes, acting as micro–message carriers, occupy an essential position in this process. Microarray analyses of exosomes revealed that miR‐221‐3p was enriched in M2 exosomes. Furthermore, miR‐221‐3p suppressed cyclin‐dependent kinase inhibitor 1B (CDKN1B) directly. Thus, miR‐221‐3p contributed to the proliferation and G1/S transition of EOC cells. Additionally, low levels of CDKN1B were associated with EOC progression and poor prognosis. These observations suggest that TAMs‐derived exosomal miR‐221‐3p acts as a regulator of EOC progression by targeting CDKN1B. The results of this study confirm that certain exosomal microRNAs may provide novel diagnostic biomarkers and therapeutic targets for EOC.