Platelets promote invasion and induce epithelial to mesenchymal transition in ovarian cancer cells by TGF-β signaling pathway

• Published in: Gynecologic oncology Vol. 153; no. 3; pp. 639 - 650
• Main Authors: Guo, Yi, Cui, Wei, Pei, Yuqing, Xu, Danfei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2019
• Subjects: A83–01; Adult; Animals; Blood Platelets; Cadherins - genetics; Cadherins - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Coculture Techniques; Epithelial to mesenchymal transition; Epithelial-Mesenchymal Transition - genetics; Female; Fibronectins - genetics; Gene Expression; Healthy Volunteers; Humans; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Mice; Middle Aged; Neoplasm Invasiveness; Neoplasm Transplantation; Ovarian cancer; Ovarian Neoplasms - blood; Ovarian Neoplasms - pathology; Platelet; Platelet Count; Pyrazoles - pharmacology; Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors; Signal Transduction; Smad Proteins - metabolism; Snail Family Transcription Factors - genetics; TGF-β; Thiosemicarbazones - pharmacology; Transforming Growth Factor beta - blood; Transforming Growth Factor beta - metabolism; Up-Regulation; Vimentin - genetics; Epithelial to mesenchymal transition; TGF-β; Platelet; A83–01; Ovarian cancer
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2019.02.026

To test whether platelets could increase invasion potential and initiate EMT in ovarian cancer cells via a TGF-β signaling pathway. Blood samples were collected in 69 patients with ovarian cancer, 16 patients with benign ovarian tumor and 64 healthy donors. SK-OV-3 and OVCAR-3 ovarian cancer cells were treated with platelets. Transwell assays were used to analyze the invasive capacity, and EMT was assessed by microarray analysis, quantitative real-time PCR (qPCR) and Western blotting. Activation of TGF-β pathway was examined by ELISA and Western blotting. TGF-β type I receptor (TβR I) inhibitor A83-01 was used to confirm the role of TGF-β pathway in vitro and in vivo. Clinical data showed ovarian cancer patients with elevated platelet counts had a higher incidence of advanced stages. Treatment with platelets increased the invasive properties of both cell lines. Mesenchymal markers (snail family transcriptional repressor-1, vimentin, neural cadherin, fibronectin-1 and matrix metalloproteinase-2) were up-regulated in platelet-treated cells, while the epithelial marker (epithelial cadherin) was down-regulated. Higher TGF-β level was observed in patients with elevated platelet counts when compared to the subjects. Higher levels of TGF-β were also found in culture medium treated with platelets, and cells treated with platelets also showed increased phosphorylation of Smad2. TβR I inhibitor A83–01 reversed the EMT-like alterations and inhibited platelet-induced invasion in vitro and in vivo. Platelet increased invasion potential and induced EMT in ovarian cancer cells in a TGF-β dependent pathway. Platelet-derived TGF-β may be useful as a new target treatment for ovarian cancer. •Ovarian cancer patients with elevated platelets showed higher incidence of metastasis.•Platelets increase invasive ability and induce EMT in ovarian cancer cells.•Serum TGF-β level was higher in ovarian cancer patients with elevated platelet.•TGF-β/Smad pathway was activated in platelet-treated ovarian cancer cells.•TGF-β type I receptor inhibitor A83-01 abolished platelets-induced invasion and EMT in vitro and in vivo.