Copper content in ascitic fluid is associated with angiogenesis and progression in ovarian cancer |
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| Affiliation: | 1. Department of Obstetrics and Gynecology, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan;2. Department of Nursing, Faculty of Nursing and Welfare Sciences, Fukui Prefectural University, Fukui, 910-1195, Japan;1. Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, and Ministry of Education (MOE) Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, PR China;2. Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong Province, 518051, PR China;1. Department of Food Science and Dietetics, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland;2. Department of Laboratory Diagnostics, Wroclaw Medical University, Borowska 211a, 50-556 Wrocław, Poland;3. 1st Department and Clinic of Gynaecology and Obstetrics, Wroclaw Medical University, T. Chałubińskiego 3, 50-368 Wrocław, Poland;4. Private Diet Clinic “DietetykaNieNaZarty”, Parkowa 25 C/53-64, 51-616 Wrocław, Poland;1. Department of Hygiene and Public Health, Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan;2. Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China;3. Beijing FangShan District Maternal and Child Health Care Hospital, Beijing 102488, China;4. Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan;5. Teikyo Graduate School of Public Health, Tokyo 173-8605, Japan;1. Center for Advanced Studies and Technology (C.A.S.T.), "G. d''Annunzio" University of Chieti-Pescara, Via Luigi Polacchi 11, Chieti, I-66100, Italy;2. Department of Physics, Università Degli Studi di Milano, Via Celoria 16, Milano, I-20133, Italy;3. LASA, Department of Physics, Università Degli Studi di Milano and INFN-Milano, Via F.lli Cervi 201, Segrate, MI, I-20090, Italy;4. Institute of Clinical Immunotherapy and Advanced Biological Treatments, Piazza Pierangeli 1, Pescara, Rectorate of Leonardo da Vinci Telematic University, Largo San Rocco 11 Torrevecchia Teatina, CH, Italy;5. Department of Medicine and Aging Sciences, "G. d''Annunzio" University of Chieti-Pescara, via Luigi Polacchi 11, Chieti, I-66100, Italy;1. Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Para, Belém, PA, Brazil;2. Laboratory of Molecular Pharmacology, Institute of Biological Sciences, Federal University of Para, Belém, PA, Brazil |
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| Abstract: | BackgroundAscites is associated with the poor prognosis of malignant tumors. The biological importance of the changes in the content of trace elements in the ascitic fluid is unknown. Herein, we analyzed trace elements in the ascitic fluid of patients with ovarian tumors and used cultured cells to determine the copper (Cu)-induced changes in gene expression in ovarian cancer.MethodsInductively coupled plasma mass spectrometry (ICP-MS) was used to compare ascitic fluid trace element levels in patients with benign ovarian tumors (n = 22) and borderline/malignant tumors (n = 5) for primary screening. Cu levels were validated using atomic absorption spectrometry (AAS) in 88 benign, 11 borderline, and 25 malignant ovarian tumor patients. To confirm Cu-induced gene expression changes, microarray analysis was performed for Cu-treated OVCAR3, A2780, and Met5A cells. The vascular endothelial growth factor (VEGF) concentration in the cell supernatant or ascitic fluid (ovarian cancer samples) was measured using ELISA.ResultsICP-MS showed that Co, Ni, Cu, Zn, As, Se, and Mo levels significantly increased in patients with malignant/borderline ovarian tumors compared to those in patients with benign ovarian tumors. AAS showed that malignant ovarian tumors were independently associated with elevated levels of Cu in ascites adjusted for age, body mass index, alcohol, smoking, and supplement use (p < 0.001). Microarray analysis of both Cu-treated ovarian cancer cell lines OVCAR3 and A2780 and the mesothelial cell line Met-5A revealed the upregulation of the angiogenesis biological process. Real-time polymerase chain reaction and ELISA demonstrated that an increased Cu content significantly enhanced VEGF mRNA expression and protein secretion in OVCAR3, A2780, and Met-5A cells. VEGF levels and clinical stages of the tumors correlated with the ascitic fluid Cu content in patients with malignant ovarian tumors (correlation coefficient 0.445, 95 % confidence interval [CI]: 0.069–0.710, p = 0.023 and correlation coefficient 0.406, 95 % CI: 0.022–0.686, p = 0.040, respectively).ConclusionCu levels significantly increased in patients with malignant ovarian cancer. Cu induced angiogenic effects in ovarian cancer and mesothelial cells, which affected ascites fluid production. This study clarifies the link between elevated Cu in ascites and malignant ovarian tumor progression. Strategies to decrease Cu levels in the ascitic fluid may help downregulate VEGF expression, thereby improving the prognosis of ovarian malignancies. |
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| Keywords: | Ovarian cancer Trace element Copper Ascites VEGF |
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