Coelho Ricardo, Ricardo Sara, Amaral Ana Luísa, Huang Yen-Lin, Nunes Mariana, Neves José Pedro, Mendes Nuno, López Mónica Nuñez, Bartosch Carla, Ferreira Verónica, Portugal Raquel, Lopes José Manuel, Almeida Raquel, Heinzelmann-Schwarz Viola, Jacob Francis, David Leonor
Differentiation and Cancer group, Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
Oncogenesis. 2020 Jul 1;9(6):61. doi: 10.1038/s41389-020-00246-2.
Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient's outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLN ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.
腹膜播散是一种在卵巢癌中常见的转移形式，也是患者预后不良的主要原因。确定参与卵巢癌播散的分子机制，可为开发改善临床预后的治疗策略提供方向。在此，我们确定间皮素（MSLN）是卵巢癌腹膜播散多步骤过程中的关键蛋白。我们发现，在高级别浆液性癌（HGSC）的原发灶及配对腹膜转移灶中，MSLN均呈过表达。通过构建多种基因工程化的卵巢癌细胞系以实现功能缺失或获得，我们发现MSLN可提高细胞在悬浮状态下的存活率，并促进肿瘤细胞在体外穿过间皮细胞层的侵袭能力。用表达MSLN的卵巢癌细胞系建立的腹腔内异种移植模型显示，肿瘤负荷增加且在腹腔内播散。这些发现有力地证明了MSLN通过引发腹膜播散，在卵巢癌进展中发挥关键作用，并为进一步将MSLN作为HGSC治疗靶点的临床研究提供了支持。
