A novel mechanism of neovascularization in peritoneal dissemination via cancer-associated mesothelial cells affected by TGF-β derived from ovarian cancer
A novel mechanism of neovascularization in peritoneal dissemination via cancer-associated mesothelial cells affected by TGF-β derived from ovarian cancer
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DOI：
10.3892/or.2017.6104
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发表时间：
2018-01-01
期刊：
影响因子：
4.2
通讯作者：
Kikawa, Fumitaka
中科院分区：
文献类型：
--
作者：
Fujikake, Kayo;Kajiyama, Hiroaki;Kikawa, Fumitaka
上皮性卵巢癌(EOC)被认为是通过肿瘤和间皮细胞之间的微环境细胞间通讯导致腹膜扩散，导致进一步获得进展和转移潜能。在本研究中，我们旨在确定肿瘤相关间皮细胞(CAMC)通过增加血管内皮生长因子(VEGF)的产生，在促进肿瘤新生血管形成和血管通透性方面的作用。我们检测了在恶性腹水和肿瘤来源的转化生长因子-β存在的情况下，人腹膜间皮细胞(HPMC)是否发生了特征性的形态变化。我们重点研究了血管内皮生长因子在血管内皮细胞迁移和血管形成中的重要作用。正常HPMC呈鹅卵石样上皮形态。当HPMCs与晚期卵巢癌患者的恶性腹水共同培养时，观察到从上皮样形态转变为α-SMA阳性的成纤维细胞间质形态。此外，我们还发现EOC来源的转化生长因子-β诱导了HPMCs典型的EMT样形态改变，这与CAMCs有关。我们进一步发现，CAMCs通过促进血管内皮生长因子的产生，在促进内皮细胞迁移和管状形成中起着至关重要的作用。综上所述，我们的研究结果提示CAMCs可能参与了EOC的新生血管形成和血管通透性增强，从而导致恶性腹水的形成。通过EoC和间皮细胞之间的微环境细胞间通讯，揭示了CAMCs作为EoC进展促进剂的新机制。
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.