Spread Of Epithelial Ovarian Cancer Research Articles

Exosomal Integrin α5β1/AEP Complex Derived from EOC Promotes Peritoneal Metastasis Through Regulating Mesothelial Cells Proliferation and Migration

Purpose: Epithelial ovarian cancer (EOC) is one of the most malignant cancer in gynecologic system. Many patients are diagnosed at advanced stage with widely disseminated intra-peritoneal metastasis. EOC spreads via direct extension and transcoelomic spread. However, the interplay between human peritoneal mesothelial cells (HPMCs) and EOC cells is ambiguous. we hypothesize that integrin in HPMCs plays an important role in tumor initial metastasis. Experimental. Design: The expression of integrin different subtypes from HPMCs was validated using WB. The integrin α5β1 high expression and colocalization with asparaginyl endopeptidase (AEP) in EOC cells and HPMCs derived from EOC patients (EOC-HPMCs) was concluded by IF. The role and mechanism of exosomal integrin α5β1/AEP complex in HPMCs was elucidated using in vitro and in vivo. A retrospective study involving 234 patients showed levels of integrin α5β1/AEP in circulating serum and ascites of EOCs patients, and the association between integrin α5β1/AEP expression and overall survival. Results: The integrin α5β1 was highly expressed and co-localized with AEP in EOC cells, and exosomal integrin α5β1/AEP complex secreted by EOC cells played an important role in the proliferation and migration of HPMCs. High levels of exosomal integrin α5β1/AEP were also found in circulating serum and ascites of EOCs patients, and the expression of integrin α5β1/AEP in EOC tissues was negatively associated with overall survival. Conclusions: EOC regulated the function of HPMCs through exosomal integrin α5β1/AEP, which might be crucial for EOC peritoneal initial metastasis. Funding Statement: This study was supported by grants from the National Science Foundation of China (81372787, 81402042, 81602280), Shanghai Municipal Health Bureau (20154Y0109), Shanghai Science and Technology Development Foundation (17411968100), and the Training plan for scientific research of Renji Hospital (RJZZ13-021). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The study protocol was reviewed and approved by the Institutional Review Board of Shanghai First Maternity and Infant Hospital, in accordance with the Declaration of Helsinki.

Hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) with primary or secondary cytoreductive surgery in the treatment of advanced epithelial ovarian cancer.

Peritoneal dissemination is the most common route of spread of epithelial ovarian cancer (EOC). Cytoreductive surgery (CRS) followed by platinum-based systemic chemotherapy is the current standard treatment in advanced stages, with suboptimal results. The aim of this study is to analyze the outcome of advanced EOC treated with CRS plus hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) combined with systemic chemotherapy. We analyze a cohort of women treated with CRS plus HIPEC for peritoneal carcinomatosis secondary to EOC from May 2007 to December 2014. We included both patients with peritoneal disease at first diagnosis of EOC and peritoneal recurrences after initial treatment. We performed 61 CRS with HIPEC procedures, 31 cases as primary treatment (4 as upfront therapy and 27 after neoadjuvant chemotherapy) and 30 as secondary treatment (recurrences). Median Peritoneal Carcinomatosis Index (PCI) was 9; the cytoreduction was optimal in 92% of the procedures. Severe morbidity (Grade III-IV of Clavien-Dindo classification) was 29.5%, without mortality. Median follow-up was 23 months and median disease-free survival (DFS) was 14 months (14 in primary surgery group and 17 in recurrence group, P=0.51). Median overall survival (OS) was 57 months; in primary surgery group, OS was 96.8% at 1 year, and 55% at 5 years, and median OS was not reached; OS in recurrence group was 89.3% at 1 year and 47.1% at 5 years, and median OS was 57 months. CRS with HIPEC is a treatment option for EOC with good results in terms of morbidity and survival, in experienced centers.

E-Cadherin fragments as potential mediators for peritoneal metastasis in advanced epithelial ovarian cancer.

Background:Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for tumour spread of epithelial ovarian cancer (EOC), possibly determined by the intercellular connecting protein E-Cadherin (E-Cad) and its fragments.Methods:Tumour tissue of 105 advanced EOC patients was evaluated for protein expression of E-Cad, β-Catenin and Calpain by western blotting and immunohistochemistry. Expression patterns were compared between tumours with solely intraperitoneal (pT3c, pN0; n=41) and tumours with retroperitoneal metastases (pT1a-3c, pN1; n=64). Lysates of the EOC cell line SKOV3 and tumour tissue from the intraperitoneal group were tested for E-Cad expression following Calpain treatment.Results:E-Cad full-length (E-Cad-FL, 120 kDa) and two major fragments at 85 kDa (E-Cad-85) and 23 kDa (E-Cad-23) were detected by western blotting. E-Cad-85 expression was significantly higher in tumours with solely intraperitoneal metastases and correlated strongly with E-Cad-23 and the protease Calpain. Calpain-mediated cleavage was identified as a potential mechanism to generate E-Cad-85 from E-Cad-FL by treating lysates from SKOV3 cells and tumour tissue with this enzyme. Increased cytoplasmic localisation of β-Catenin in tumours with high E-Cad-85 expression corroborates that E-Cad-85 loses the binding site for β-Catenin after fragmentation, enabling tumour cluster formation and peritoneal dissemination.Conclusions:Calpain-mediated E-Cad fragmentation appears to promote intraperitoneal EOC progression. Understanding these mechanisms might eventually lead to new tailored subtype-specific diagnostic and therapeutic interventions.

Emerging Roles of Kruppel‐Like Factor 6 and Kruppel‐Like Factor 6 Splice Variant 1 in Ovarian Cancer Progression and Treatment

Epithelial ovarian cancer is one of the most lethal gynecologic cancers and the fifth most frequent cause of female cancer deaths in the United States. Despite dramatic treatment successes in other cancers through the use of molecular agents targeted against genetically defined events driving cancer development and progression, very few insights into epithelial ovarian cancer have been translated from the laboratory to the clinic. If advances are to be made in the early diagnosis, prevention, and treatment of this disease, it will be critical to characterize the common and private (personalized) genetic defects underlying the development and spread of epithelial ovarian cancer. The tumor suppressor Kruppel-like factor 6 and its alternatively spliced, oncogenic isoform, Kruppel-like factor 6 splice variant 1, are members of the Kruppel-like zinc finger transcription factor family of proteins, which have diverse roles in cellular differentiation, development, proliferation, growth-related signal transduction, and apoptosis. Inactivation of Kruppel-like factor 6 and overexpression of Kruppel-like factor 6 splice variant 1 have been associated with the progression of a number of human cancers and even with patient survival. This article summarizes our recent findings demonstrating that a majority of epithelial ovarian cancer tumors have Kruppel-like factor 6 allelic loss and decreased expression coupled with increased expression of Kruppel-like factor 6 splice variant 1. The targeted reduction of Kruppel-like factor 6 in ovarian cancer cell lines results in marked increases in cell proliferation, invasion, tumor growth, angiogenesis, and intraperitoneal dissemination in vivo. In contrast, the inhibition of Kruppel-like factor 6 splice variant 1 decreases cellular proliferation, invasion, angiogenesis, and tumorigenicity; this provides the rationale for its potential therapeutic application. These results and our recent demonstration that the inhibition of Kruppel-like factor 6 splice variant 1 can dramatically prolong survival in a preclinical mouse model of ovarian cancer are reviewed and discussed.