Fang Dong, Kitamura Hiroshi
Department of Urology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China.
Int J Urol. 2018 Jan;25(1):7-17. doi: 10.1111/iju.13404. Epub 2017 Jul 11.
There is growing evidence of the presence of cancer stem cells in urothelial carcinoma. Cancer stem cells have the ability to self-renew and to differentiate into all cell types of the original heterogeneous tumor. A panel of diverse cancer stem cell markers might be suitable for simulation studies of urothelial cancer stem cells and for the development of optimized treatment protocols. The present review focuses on the advances in recognizing the markers of urothelial cancer stem cells and possible therapeutic targets. The commonly reported markers and pathways that were evaluated include CD44, CD133, ALDH1, SOX2 & SOX4, BMI1, EZH1, PD-L1, MAGE-A3, COX2/PGE2/STAT3, AR, and autophagy. Studies on the epithelial-mesenchymal transition-related pathways (Shh, Wnt/β-catenin, Notch, PI3K/Akt, TGF-β, miRNA) are also reviewed. Most of these markers were recognized through the expression patterns of cancer stem cell-rich side populations. Their regulative role in the development and differentiation of urothelial cancer stem cells was confirmed in vitro by functional analyses (e.g. cell migration, colony formation, sphere formation), and in vivo in xenograft experiments. Although a small number of these pathways are targeted by currently available drugs or drugs that are the currently being tested in clinical trials, a clear treatment approach has not been developed for most pathways. A greater understanding of the mechanisms that control the proliferation and differentiation of cancer stem cells is expected to lead to improvements in targeted therapy.
越来越多的证据表明尿路上皮癌中存在癌症干细胞。癌症干细胞具有自我更新能力，并能分化为原始异质性肿瘤的所有细胞类型。一组多样的癌症干细胞标志物可能适用于尿路上皮癌干细胞的模拟研究以及优化治疗方案的制定。本综述聚焦于识别尿路上皮癌干细胞标志物及可能的治疗靶点方面的进展。所评估的常见报道标志物和途径包括CD44、CD133、醛脱氢酶1（ALDH1）、性别决定区Y框蛋白2（SOX2）和性别决定区Y框蛋白4（SOX4）、BMI1、EZH1、程序性死亡受体配体1（PD-L1）、黑色素瘤抗原基因A3（MAGE-A3）、环氧化酶2（COX2）/前列腺素E2（PGE2）/信号转导和转录激活因子3（STAT3）、雄激素受体（AR）以及自噬。上皮-间质转化相关途径（音猬因子（Shh）、Wnt/β-连环蛋白、Notch、磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（Akt）、转化生长因子-β（TGF-β）、微小RNA（miRNA））的研究也在本综述中进行了阐述。这些标志物大多是通过富含癌症干细胞的侧群细胞的表达模式得以识别。它们在尿路上皮癌干细胞发育和分化中的调控作用通过功能分析（如细胞迁移、集落形成、球体形成）在体外得以证实，并在异种移植实验中在体内得以证实。尽管目前有少数这些途径可被现有药物或正在临床试验中测试的药物靶向，但对于大多数途径尚未形成明确的治疗方法。对控制癌症干细胞增殖和分化机制的更深入理解有望带来靶向治疗的改进。
