Department of Cellular and Molecular Medicine, University of Ottawa , Ottawa, ON , Canada ; Centre for Cancer Therapeutics, Ottawa Hospital Research Institute , Ottawa, ON , Canada.
Centre for Cancer Therapeutics, Ottawa Hospital Research Institute , Ottawa, ON , Canada ; Department of Pathology and Laboratory Medicine, University of Ottawa , Ottawa, ON , Canada.
Front Oncol. 2014 Mar 18;4:53. doi: 10.3389/fonc.2014.00053. eCollection 2014.
Improving screening and treatment options for patients with epithelial ovarian cancer has been a major challenge in cancer research. Development of novel diagnostic and therapeutic approaches, particularly for the most common subtype, high-grade serous ovarian cancer (HGSC), has been hampered by controversies over the origin of the disease and a lack of spontaneous HGSC models to resolve this controversy. Over long-term culture in our laboratory, an ovarian surface epithelial (OSE) cell line spontaneously transformed OSE (STOSE). The objective of this study was to determine if the STOSE cell line is a good model of HGSC. STOSE cells grow faster than early passage parental M0505 cells with a doubling time of 13 and 48 h, respectively. STOSE cells form colonies in soft agar, an activity for which M0505 cells have negligible capacity. Microarray analysis identified 1755 down-regulated genes and 1203 up-regulated genes in STOSE compared to M0505 cells, many associated with aberrant Wnt/β-catenin and Nf-κB signaling. Upregulation of Ccnd1 and loss of Cdkn2a in STOSE tumors is consistent with changes identified in human ovarian cancers by The Cancer Genome Atlas. Intraperitoneal injection of STOSE cells into severe combined immunodeficient and syngeneic FVB/N mice produced cytokeratin+, WT1+, inhibin-, and PAX8+ tumors, a histotype resembling human HGSC. Based on evidence that a SCA1+ stem cell-like population exists in M0505 cells, we examined a subpopulation of SCA1+ cells that is present in STOSE cells. Compared to SCA1- cells, SCA1+ STOSE cells have increased colony-forming capacity and form palpable tumors 8 days faster after intrabursal injection into FVB/N mice. This study has identified the STOSE cells as the first spontaneous murine model of HGSC and provides evidence for the OSE as a possible origin of HGSC. Furthermore, this model provides a novel opportunity to study how normal stem-like OSE cells may transform into tumor-initiating cells.
提高上皮性卵巢癌患者的筛查和治疗选择一直是癌症研究的主要挑战。新的诊断和治疗方法的发展，特别是对于最常见的亚型——高级别浆液性卵巢癌（HGSC），由于对疾病起源的争议以及缺乏自发的 HGSC 模型来解决这一争议，一直受到阻碍。在我们的实验室中，经过长期培养，卵巢表面上皮（OSE）细胞系自发转化为 OSE（STOSE）。本研究的目的是确定 STOSE 细胞系是否是 HGSC 的良好模型。STOSE 细胞的生长速度比早期传代的亲本 M0505 细胞快，倍增时间分别为 13 和 48 小时。STOSE 细胞在软琼脂中形成集落，而 M0505 细胞几乎没有这种能力。微阵列分析显示，与 M0505 细胞相比，STOSE 中有 1755 个下调基因和 1203 个上调基因，其中许多与异常的 Wnt/β-catenin 和 NF-κB 信号通路有关。STOSE 肿瘤中 Ccnd1 的上调和 Cdkn2a 的缺失与癌症基因组图谱鉴定的人类卵巢癌中的变化一致。将 STOSE 细胞腹腔内注射到严重联合免疫缺陷和同基因 FVB/N 小鼠中，产生了角蛋白+、WT1+、抑制素-和 PAX8+的肿瘤，其组织类型类似于人类 HGSC。基于 SCA1+干细胞样群体存在于 M0505 细胞中的证据，我们研究了 STOSE 细胞中存在的 SCA1+细胞的亚群。与 SCA1-细胞相比，SCA1+ STOSE 细胞具有更高的集落形成能力，并且在 FVB/N 小鼠中通过囊内注射后 8 天更快地形成可触及的肿瘤。本研究将 STOSE 细胞鉴定为第一个自发的 HGSC 小鼠模型，并为 OSE 可能是 HGSC 的起源提供了证据。此外，该模型为研究正常干细胞样 OSE 细胞如何转化为肿瘤起始细胞提供了新的机会。
