Ovarian cancer (OvCa), a lethal gynecological malignancy, disseminates to the peritoneum. Mesothelial cells (MCs) act as barriers in the abdominal cavity, preventing the adhesion of cancer cells. However, in patients with OvCa, they are transformed into cancer-associated mesothelial cells (CAMs) via mesenchymal transition and form a favorable microenvironment for tumors to promote metastasis. However, attempts for restoring CAMs to their original state have been limited. Here, we investigated whether inhibition of mesenchymal transition and restoration of MCs by vitamin D suppressed the OvCa dissemination in vitro and in vivo. The effect of vitamin D on the mutual association of MCs and OvCa cells was evaluated using in vitro coculture models and in vivo using a xenograft model. Vitamin D restored the CAMs, and thrombospondin-1 (component of the extracellular matrix that is clinically associated with poor prognosis and is highly expressed in peritoneally metastasized OvCa) was found to promote OvCa cell adhesion and proliferation. Mechanistically, TGF-β1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-β signaling. Vitamin D inhibited mesenchymal transition in MCs and suppressed thrombospondin-1 expression via vitamin D receptor/Smad3 competition, contributing to the marked reduction in peritoneal dissemination in vivo. Importantly, vitamin D restored CAMs from a stabilized mesenchymal state to the epithelial state and normalized thrombospondin-1 expression in preclinical models that mimic cancerous peritonitis in vivo. MCs are key players in OvCa dissemination and peritoneal restoration and normalization of thrombospondin-1 expression by vitamin D may be a novel strategy for preventing OvCa dissemination.

卵巢癌 (OvCa) 是一种致命的妇科恶性肿瘤，会播散至腹膜。间皮细胞 (MC) 在腹腔中充当屏障，防止癌细胞粘附。然而，在 OvCa 患者中，它们通过间充质转化转化为癌症相关间皮细胞 (CAM)，并为肿瘤形成有利的微环境以促进转移。然而，将 CAM 恢复到其原始状态的尝试受到限制。在这里，我们研究了维生素 D 对间充质转化的抑制和 MCs 的恢复是否抑制了 OvCa在体外和体内的传播。使用体外共培养模型评估维生素 D 对 MCs 和 OvCa 细胞相互结合的影响体内使用异种移植模型。维生素 D 恢复了 CAM，发现血小板反应蛋白-1（细胞外基质的成分，临床上与预后不良相关，在腹膜转移的 OvCa 中高表达）促进 OvCa 细胞粘附和增殖。从机制上讲，OvCa 细胞分泌的 TGF-β1 通过 Smad 依赖性 TGF-β 信号传导增强 CAMs 中血小板反应蛋白-1 的表达。维生素 D 通过维生素 D 受体/Smad3 竞争抑制 MC 的间充质转化并抑制血小板反应蛋白-1 的表达，有助于显着减少体内腹膜传播. 重要的是，在模拟体内癌性腹膜炎的临床前模型中，维生素 D 将 CAM 从稳定的间充质状态恢复到上皮状态，并使血小板反应蛋白-1 表达正常化。MC 是 OvCa 传播和腹膜恢复的关键参与者，维生素 D 使血小板反应蛋白-1 表达正常化可能是预防 OvCa 传播的新策略。