Gupta Piyush B, Onder Tamer T, Jiang Guozhi, Tao Kai, Kuperwasser Charlotte, Weinberg Robert A, Lander Eric S
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
由于上皮癌干细胞（CSCs）在肿瘤细胞群体中数量稀少且在培养中相对不稳定，因此无法对特异性杀死这些细胞的药物进行筛选。我们在此描述一种筛选具有上皮CSC特异性毒性药物的方法。我们在化学筛选中实施了该方法，并发现了对乳腺CSCs具有选择性毒性的化合物。一种化合物，盐霉素，相对于常用的乳腺癌化疗药物紫杉醇，可将CSCs的比例降低100倍以上。用盐霉素治疗小鼠可抑制体内乳腺肿瘤生长，并诱导肿瘤细胞上皮分化增加。此外，全基因组表达分析表明，盐霉素治疗导致先前通过对直接从患者分离的乳腺组织分析鉴定出的乳腺CSC基因表达丧失。这项研究证明了识别对上皮CSCs具有特异性毒性药物的能力。
