Malek Reem, Wang Hailun, Taparra Kekoa, Tran Phuoc T
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cells Tissues Organs. 2017;203(2):114-127. doi: 10.1159/000447238. Epub 2017 Feb 20.
Mounting data points to epithelial plasticity programs such as the epithelial-mesenchymal transition (EMT) as clinically relevant therapeutic targets for the treatment of malignant tumors. In addition to the widely realized role of EMT in increasing cancer cell invasiveness during cancer metastasis, the EMT has also been implicated in allowing cancer cells to avoid tumor suppressor pathways during early tumorigenesis. In addition, data linking EMT to innate and acquired treatment resistance further points towards the desire to develop pharmacological therapies to target epithelial plasticity in cancer. In this review we organized our discussion on pathways and agents that can be used to target the EMT in cancer into 3 groups: (1) extracellular inducers of EMT, (2) the transcription factors that orchestrate the EMT transcriptome, and (3) the downstream effectors of EMT. We highlight only briefly specific canonical pathways known to be involved in EMT, such as the signal transduction pathways TGFβ, EFGR, and Axl-Gas6. We emphasize in more detail pathways that we believe are emerging novel pathways and therapeutic targets such as epigenetic therapies, glycosylation pathways, and immunotherapy. The heterogeneity of tumors and the dynamic nature of epithelial plasticity in cancer cells make it likely that targeting only 1 EMT-related process will be unsuccessful or only transiently successful. We suggest that with greater understanding of epithelial plasticity regulation, such as with the EMT, a more systematic targeting of multiple EMT regulatory networks will be the best path forward to improve cancer outcomes.
越来越多的数据表明，上皮可塑性程序，如上皮-间质转化（EMT），是治疗恶性肿瘤的临床相关治疗靶点。除了EMT在癌症转移过程中增加癌细胞侵袭性方面广为人知的作用外，EMT还与癌细胞在肿瘤发生早期逃避肿瘤抑制途径有关。此外，将EMT与先天性和获得性治疗耐药性联系起来的数据进一步表明，开发针对癌症上皮可塑性的药物治疗方法的愿望。在这篇综述中，我们将关于可用于靶向癌症中EMT的途径和药物的讨论分为3组：（1）EMT的细胞外诱导剂，（2）协调EMT转录组的转录因子以及（3）EMT的下游效应器。我们仅简要强调已知参与EMT的特定经典途径，如信号转导途径TGFβ、EFGR和Axl-Gas6。我们更详细地强调我们认为正在出现的新途径和治疗靶点，如表观遗传疗法、糖基化途径和免疫疗法。肿瘤的异质性和癌细胞中上皮可塑性的动态性质使得仅靶向1个与EMT相关的过程可能不会成功或只是暂时成功。我们建议，随着对上皮可塑性调节（如EMT）的更深入了解，更系统地靶向多个EMT调节网络将是改善癌症治疗效果的最佳前进道路。
