Abstract
PurposeEpithelial 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 trans-coelomic 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.MethodsThe 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.ResultsWe 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.ConclusionsOur data indicate that EOCs may regulate the function of HPMCs through exosomal ITGA5B1/AEP, which may be crucial for peritoneal metastasis.
Highlights
Epithelial ovarian cancer (EOC) is one of the most malignant cancers occurring in the gynecologic system
We found that human peritoneal mesothelial cells (HPMCs) regulation through the EOC exosomal ITGA5B1/asparaginyl endopeptidase (AEP) complex may be a crucial step in EOC peritoneal metastasis
We found that the ITGA5B1/AEP complex may serve as a new biomarker and/ or therapeutic target for EOC patients
Summary
Epithelial ovarian cancer (EOC) is one of the most malignant cancers occurring in the gynecologic system. In the United States alone, each year > 22,000 new patients are diagnosed with EOC and > 14,000 patients die from it [1]. It is difficult to diagnose EOC in its early stages because of a lack of comprehensive laboratory tests and specific symptoms [2, 3]. More than half of the EOC patients are diagnosed at advanced stages with widespread metastases. The key components of EOC progression are peritoneal dissemination, multiple organ metastases, refractory ascites and retroperitoneal lymph node involvement [5, 6]. The diagnosis of EOC recurrence and metastasis mainly relies on detection of the biomarker carbohydrate antigen 125 (CA125) [7] combined with medical imaging clues, which are limited in specificity and sensitivity. New biomarkers are urgently needed for early EOC and metastasis detection
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