Modulation of AKT activity is associated with reversible dormancy in ascites-derived epithelial ovarian cancer spheroids
Modulation of AKT activity is associated with reversible dormancy in ascites-derived epithelial ovarian cancer spheroids
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DOI：
10.1093/carcin/bgr241
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发表时间：
2012-01-01
期刊：
影响因子：
4.7
通讯作者：
Shepherd, Trevor G.
中科院分区：
文献类型：
--
作者：
Correa, Rohann J. M.;Peart, Teresa;Shepherd, Trevor G.
上皮性卵巢癌（EOC）转移是导致该疾病患者高复发率和低生存率的直接因素。EOC中的转移通过细胞从原发性肿瘤脱落到充满液体的腹膜腔中、这些细胞作为非粘附性多细胞聚集体或球状体持续存在以及球状体再附着以形成继发性病变而发生。我们已经从腹水中回收了天然球状体，并证明这些结构中的EOC细胞表现出增殖减少，但重新获得附着和重新启动细胞分裂的能力。为了在体外模拟该过程以用于进一步研究，在非粘附条件下培养来自患者腹膜液的原代EOC细胞。在这里，我们表明，这些细胞自然形成类似于腹水中观察到的球体。球状体表现出细胞增殖减少和与细胞静止一致的蛋白质表达模式：特别是磷酸化AKT和p45/SKP 2减少，同时p130/RBL 2和p27（Kip 1）增加。然而，当球状体接种到粘附表面时，重新附着迅速发生，随后是AKT依赖性细胞增殖的重新启动。这些结果在许多临床标本中惊人地一致，并在EOC细胞系OVCAR 3中得到证实。因此，我们的数据表明，EOC细胞成为静止时，形成球状体，但重新激活增殖机制后，附件到一个允许的基质。总的来说，这项工作利用了一种新的体外模型的EOC转移，采用原代人EOC细胞，并介绍了重要的概念，可逆休眠的EOC发病机制。
Epithelial ovarian cancer (EOC) metastasis is a direct contributor to high recurrence and low survival for patients with this disease. Metastasis in EOC occurs by cell exfoliation from the primary tumor into the fluid-filled peritoneal cavity, persistence of these cells as non-adherent multicellular aggregates or spheroids and reattachment of spheroids to form secondary lesions. We have recovered native spheroids from ascites fluid and demonstrated that EOC cells within these structures exhibit reduced proliferation, yet regain the capacity to attach and reinitiate cell division. To model this process in vitro for further investigation, primary EOC cells from patient peritoneal fluid were cultured under non-adherent conditions. Here we show that these cells naturally form spheroids resembling those observed in ascites. Spheroids exhibit reduced cell proliferation and a protein expression pattern consistent with cellular quiescence: specifically, decreased phospho-AKT and p45/SKP2 with a concomitant increase in p130/RBL2 and p27(Kip1). However, when spheroids are seeded to an adherent surface, reattachment occurs rapidly and is followed by reinitiation of AKT-dependent cell proliferation. These results were strikingly consistent among numerous clinical specimens and were corroborated in the EOC cell line OVCAR3. Therefore, our data reveal that EOC cells become quiescent when forming spheroids, but reactivate proliferative mechanisms upon attachment to a permissive substratum. Overall, this work utilizes a novel in vitro model of EOC metastasis that employs primary human EOC cells and introduces the important concept of reversible dormancy in EOC pathogenesis.