Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis
Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis
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DOI：
10.1016/j.matbio.2022.03.003
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发表时间：
2022-04-08
期刊：
影响因子：
6.9
通讯作者：
Kajiyama, Hiroaki
中科院分区：
文献类型：
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作者：
Kitami, Kazuhisa;Yoshihara, Masato;Kajiyama, Hiroaki
卵巢癌（OvCa）是一种致命的妇科恶性肿瘤，可扩散至腹膜。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的间皮细胞（CAM），并形成肿瘤促进转移的有利微环境。然而，将CAM恢复到其原始状态的尝试是有限的。在这里，我们研究了维生素D抑制间充质转化和恢复MCs是否抑制OvCa在体外和体内的传播。使用体外共培养模型和体内异种移植模型评价维生素D对MC和OvCa细胞相互结合的影响。维生素D恢复了CAM，并且发现血小板反应蛋白-1（临床上与不良预后相关并且在腹膜转移的OvCa中高度表达的细胞外基质的组分）促进OvCa细胞粘附和增殖。从机制上讲，OvCa细胞分泌的TGF-β 1通过Smad依赖性TGF-β信号传导增强CAM中的血小板反应蛋白-1表达。维生素D通过维生素D受体/Smad 3竞争抑制MCs的间质转化和血小板反应蛋白-1的表达，有助于体内腹膜播散的显著减少。重要的是，维生素D在模拟体内癌性腹膜炎的临床前模型中将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。(C)2022作者。出版社：Elsevier B. V. This
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-beta 1 secreted from OvCa cells enhanced thrombospondin-1 expression in CAMs via Smad-dependent TGF-beta 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. (C) 2022 The Author(s). Published by Elsevier B.V. This