Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Int J Cancer. 2020 Apr 15;146(8):2268-2280. doi: 10.1002/ijc.32854. Epub 2020 Jan 24.
Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell-to-cell crosstalk or phenotypic alterations including the acquisition of platinum-resistance in OvCa cells. Herein, we report how OvCa-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.
卵巢癌（OvCa）的腹膜播散源于腹膜表面，由单层间皮细胞（MCs）覆盖。鉴于 OvCa 细胞和 MCs 都存在于相同的腹膜转移微环境中，它们可能会建立细胞间通讯或表型改变，包括 OvCa 细胞获得铂耐药性。在此，我们报告了 OvCa 相关间皮细胞（OCAMs）如何通过直接细胞间通讯诱导 OvCa 细胞获得铂耐药性。我们通过体外共培养实验模型和基于组学的数据分析评估了 OvCa 细胞与人类原代 MCs 之间的相互关联。还使用临床样本和体内小鼠模型研究了 OCAMs 的作用。体外实验结果表明，TGF-β1 刺激主要诱导 OCAMs 发生间质转化。此外，OCAMs 作为腹膜转移肿瘤微环境的一部分，影响 OvCa 细胞的行为。从机制上讲，OCAMs 可以通过细胞间相互作用诱导 FN1/Akt 信号通路诱导 OvCa 细胞铂敏感性降低。对 OvCa 腹膜转移的组织学分析也说明了 FN1 在来源于 MCs 的基质细胞中的表达。此外，我们还使用体内小鼠模型证实了与 TGF-β1 刺激的腹膜接触的 OvCa 细胞中 Akt 信号的激活。我们的研究结果表明，由 OvCa 细胞和 OCAMs 之间的直接细胞间通讯增强的肿瘤微环境，诱导 OvCa 细胞获得铂耐药性，这可能成为预防 OvCa 腹膜播散的新治疗靶点。
