Gazda Lawrence S, Martis Prithy C, Laramore Melissa A, Bautista Melissa A, Dudley Atira, Vinerean Horatiu V, Smith Barry H
The Rogosin Institute; New York, NY USA; The Rogosin Institute-Xenia Division; Xenia, OH USA.
The Rogosin Institute-Xenia Division; Xenia, OH USA.
Cancer Biol Ther. 2013 Dec;14(12):1147-57. doi: 10.4161/cbt.26455. Epub 2013 Sep 12.
The cancer stem cell (CSC) theory depicts such cells as having the capacity to produce both identical CSCs (symmetrical division) and tumor-amplifying daughter cells (asymmetric division). CSCs are thought to reside in niches similar to those of normal stem cells as described for neural, intestinal, and epidermal tissue, are resistant to chemotherapy, and are responsible for tumor recurrence. We recently described the niche-like nature of mouse renal adenocarcinoma (RENCA) cells following encapsulation in agarose macrobeads. In this paper we tested the hypothesis that encapsulated RENCA colonies function as an in vitro model of a CSC niche and that the majority of cells would undergo chemotherapy-induced death, followed by tumor recurrence. After exposure to docetaxel (5 µg/ml), 50% of cells were lost one week post-treatment while only one or two cells remained in each colony by 6 weeks. Surviving cells expressed OCT4 and reformed tumors at 16 weeks post-treatment. Docetaxel-resistant cells also grew as monolayers in cell culture (16-17 weeks post-exposure) or as primary tumors following transplantation to Balb/c mice (6 of 10 mice) or NOD.CB17-Prkdc(scid)/J mice (9 of 9 mice; 10 weeks post-transplantation or 28 weeks post-exposure). These data support the hypothesis that a rare subpopulation of OCT4(+) cells are resistant to docetaxel and these cells are sufficient for tumor recurrence. The reported methodology can be used to obtain purified populations of tumor-initiating cells, to screen for anti-tumor-initiating cell agents, and to investigate the in vitro correlate of a CSC niche, especially as it relates to chemo-resistance and tumor recurrence.
癌症干细胞（CSC）理论认为，此类细胞既能产生相同的癌症干细胞（对称分裂），也能产生肿瘤增殖子代细胞（不对称分裂）。人们认为，癌症干细胞所处的微环境与神经、肠道和表皮组织中描述的正常干细胞微环境相似，对化疗具有抗性，并导致肿瘤复发。我们最近描述了小鼠肾腺癌（RENCA）细胞在被包裹于琼脂糖大珠后的类微环境特性。在本文中，我们验证了以下假设：被包裹的RENCA集落可作为癌症干细胞微环境的体外模型，并且大多数细胞会在化疗诱导下死亡，随后肿瘤复发。在用多西他赛（5 µg/ml）处理后，50%的细胞在处理后一周内消失，而到6周时每个集落中仅剩下一两个细胞。存活的细胞表达OCT4，并在处理后16周时重新形成肿瘤。对多西他赛耐药的细胞在细胞培养中（暴露后16 - 17周）也能形成单层生长，或者在移植到Balb/c小鼠（10只小鼠中有6只）或NOD.CB17 - Prkdc(scid)/J小鼠（9只小鼠中有9只；移植后10周或暴露后28周）后形成原发性肿瘤。这些数据支持了以下假设：一小部分罕见的OCT4(+)细胞对多西他赛具有抗性，并且这些细胞足以导致肿瘤复发。所报道的方法可用于获得纯化的肿瘤起始细胞群体，筛选抗肿瘤起始细胞的药物，并研究癌症干细胞微环境的体外相关性，特别是与化疗抗性和肿瘤复发相关的方面。
