A novel mechanism of neovascularization in peritoneal dissemination via cancer-associated mesothelial cells affected by TGF-β derived from ovarian cancer

Epithelial ovarian cancer (EOC) is believed to cause peritoneum dissemination through microenvironmental cell-to-cell communication between the tumor and mesothelium, leading to the further acquisition of progressive and metastatic potentials. In the present study, we aimed to determine the role of cancer-associated mesothelial cells (CAMCs) in the promotion of tumor neovascularization and vascular permeability via enhanced vascular endothelial growth factor (VEGF) production. We examined whether a characteristic morphological change in human peritoneal mesothelial cells (HPMCs) was observed in the presence of malignant ascites and tumor-derived TGF-beta. We focused on the enhanced production of VEGF in CAMCs and its crucial role in endothelial migration and tube formation. Normal HPMCs showed an epithelial morphology with a cobblestone appearance. When HPMCs were co-cultured with malignant ascites from patients with advanced EOC, a dramatic morphologic change was noted from an epithelioid pattern to an alpha-SMA-positive fibroblastic, mesenchymal pattern. Additionally, we found that EOC-derived TGF-beta induced typical EMT-like morphological alteration in HPMCs, which was associated with CAMCs. We further discovered that CAMCs play a crucial role in the enhanced migration and tube formation of endothelial cells by the promotion of VEGF production. In conclusion, our findings indicate the possible involvement of CAMCs in the neovascularization of EOC and enhancement of vascular permeability, resulting in the formation of malignant ascites. The novel mechanism of CAMCs as a facilitator of EOC progression is displayed by microenvironmental cell-to-cell communication between EOC and the mesothelium.