人腹膜间皮细胞与浆液性卵巢癌细胞球的相互作用——腹膜间皮的机械和旁分泌屏障功能的证据。

Interactions of human peritoneal mesothelial cells with serous ovarian cancer cell spheroids--evidence for a mechanical and paracrine barrier function of the peritoneal mesothelium.

机构信息

*Institute of Pathology, Kantonsspital Baden AG, Baden, Switzerland; Departments of †Pathology, ‡Gynecology and Obstetrics, and §Internal Medicine, Innsbruck Medical University, Innsbruck, Austria; ∥Department of Clinical Chemistry, Robert Bosch Hospital, Stuttgart, Germany; and ¶Institute of Pathology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.

出版信息

Int J Gynecol Cancer. 2014 Feb;24(2):192-200. doi: 10.1097/IGC.0000000000000036.

DOI:10.1097/IGC.0000000000000036

PMID:24407573

Abstract

BACKGROUND

Ovarian carcinoma spreads by implantation of tumor cells onto the peritoneal mesothelium. We established a 3-dimensional coculture model to simulate the interactions of ovarian carcinoma cell aggregates with human peritoneal mesothelial cells (HPMC).

METHODS

Multicellular tumor spheroids (MCTS) of the human ovarian cancer cell line SK-OV-3 were directly inoculated onto either confluent HPMC monolayers or their submesothelial matrix or were cocultured with mesothelium without direct cellular contact.

RESULTS AND DISCUSSIONS

Inoculation of MCTS onto submesothelial matrix resulted in rapid attachment (within 30 minutes) of the tumor cell aggregates followed by rapid dissemination (within 12 hours) and growth of tumor cells. Intact mesothelium increased the time required for MCTS attachment (up to 180 minutes) and led to almost complete inhibition of tumor cell dissemination and to 47% tumor growth suppression. Bromodeoxyuridine incorporation into tumor cell nuclei was almost completely abolished in cocultured MCTS. Growth also was inhibited in MCTS treated with supernatants of HPMC. Analysis of coculture supernatants revealed that HPMC-derived transforming growth factor β (TGF-β) was almost completely bound by MCTS. Addition of a function-blocking anti-TGF-β antibody (30 μg/mL) to the cocultures abrogated the growth inhibitory effect of the mesothelium by 50%.

CONCLUSIONS

The present model provides a dynamic system to study the complex interactions of ovarian carcinoma cells with HPMC over extended periods and suggests that the mesothelium constitutes a mechanical and partly TGF-β-mediated paracrine barrier to the progression of ovarian cancer.

摘要

背景

卵巢癌通过将肿瘤细胞植入腹膜间皮扩散。我们建立了一个 3 维共培养模型来模拟卵巢癌细胞聚集体与人腹膜间皮细胞（HPMC）的相互作用。

方法

将人卵巢癌细胞系 SK-OV-3 的多细胞肿瘤球体（MCTS）直接接种到汇合的 HPMC 单层或其亚膜下基质上，或与间皮细胞进行共培养而不进行直接细胞接触。

结果和讨论

将 MCTS 接种到亚膜下基质上，肿瘤细胞聚集体迅速附着（在 30 分钟内），随后迅速扩散（在 12 小时内）并生长。完整的间皮增加了 MCTS 附着所需的时间（最多 180 分钟），并导致肿瘤细胞扩散几乎完全被抑制，肿瘤生长抑制率为 47%。溴脱氧尿苷掺入肿瘤细胞核几乎完全被抑制在共培养的 MCTS 中。用 HPMC 上清液处理的 MCTS 也受到抑制。对共培养上清液的分析表明，HPMC 衍生的转化生长因子β（TGF-β）几乎完全被 MCTS 结合。向共培养物中添加 30μg/mL 的功能阻断抗 TGF-β 抗体，可使间皮的生长抑制作用降低 50%。