Center for Research on Early Detection and Cure of Ovarian Cancer, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cancer Res. 2010 Nov 15;70(22):9463-72. doi: 10.1158/0008-5472.CAN-10-2388. Epub 2010 Nov 2.
A relatively rare aldehyde dehydrogenase 1 (ALDH1)-positive "stem cell-like" subpopulation of tumor cells has the unique ability to initiate and perpetuate tumor growth; moreover, it is highly resistant to chemotherapy and significantly associated with poor clinical outcomes. The development of more effective therapies for cancer requires targeting of this cell population. Using cDNA microarray analysis, we identified that the expression of the Caenorhabditis elegans lin-28 homologue (LIN28) was positively correlated with the percentage of ALDH1+ tumor cells; this was further validated in an independent set of tissue arrays (n=197). Both loss-of-function and gain-of-function studies showed that LIN28 plays a critical role in the maintenance of ALDH1+ tumor cells. In addition, we found that there is a double-negative feedback loop between LIN28 and let-7 in tumor cells, and that let-7 negatively regulates ALDH1+ tumor cells. Finally, we report that a LIN28/let-7 loop modulates self-renewal and differentiation of mammary gland epithelial progenitor cells. Our data provide evidence that cancer stem cells may arise through a "reprogramming-like" mechanism. A rebalancing of the LIN28/let-7 regulatory loop could be a novel therapeutic strategy to target ALDH1+ cancer stem cells.
肿瘤细胞中相对罕见的醛脱氢酶 1（ALDH1）阳性“干细胞样”亚群具有启动和维持肿瘤生长的独特能力；此外，它对化疗具有高度抗性，并与不良的临床结果密切相关。开发更有效的癌症治疗方法需要针对该细胞群体。通过 cDNA 微阵列分析，我们发现秀丽隐杆线虫 lin-28 同源物（LIN28）的表达与 ALDH1+肿瘤细胞的百分比呈正相关；在独立的组织阵列（n=197）中进一步验证了这一点。功能丧失和功能获得研究均表明，LIN28 在维持 ALDH1+肿瘤细胞中起着关键作用。此外，我们发现肿瘤细胞中存在 LIN28 和 let-7 之间的双重负反馈回路，let-7 负调控 ALDH1+肿瘤细胞。最后，我们报告说 LIN28/let-7 循环调节乳腺上皮祖细胞的自我更新和分化。我们的数据提供了证据表明，癌症干细胞可能通过“重编程样”机制产生。重新平衡 LIN28/let-7 调节回路可能是针对 ALDH1+癌症干细胞的新型治疗策略。
