Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.
Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.
复制标题
表型可塑性决定了口腔鳞状细胞癌的癌症干细胞治疗耐药性。
DOI：
10.1016/j.ebiom.2016.01.007
复制
发表时间：
2016-02
期刊：
影响因子：
11.1
通讯作者：
Mackenzie IC
中科院分区：
文献类型：
--
作者：
Biddle A;Gammon L;Liang X;Costea DE;Mackenzie IC
癌症干细胞（CSC）驱动肿瘤扩散和治疗抗性，并且可以经历上皮-间充质转化（EMT）和间充质-上皮转化（MET）以在上皮和后EMT亚群之间切换。研究口腔鳞状细胞癌（OSCC），我们现在发现，增加的表型可塑性，经历EMT/MET的能力，是上皮细胞和EMT后亚群中CSC治疗抗性增加的基础。具有可塑性的EMT后CSC表现出特别增强的治疗抗性，并由CD 44 highEpCAM低/− CD 24+细胞表面标志物谱定义。用TGFβ和视黄酸（RA）处理能够富集该亚群用于治疗测试，通过该测试，内质网（ER）应激子和自噬抑制剂Thapsigargin显示出选择性靶向这些细胞。表型可塑性和治疗抗性之间的联系的证明，以及用于富集高度抗性CSC亚群的体外方法的开发，为开发可以消除CSC的改进的化学治疗剂提供了机会。癌症干细胞可塑性与EMT交叉以确定治疗抗性。TGFβ和RA的共同治疗富集了可塑性和耐药性癌症干细胞亚群，用于治疗测试。Thapsigargin特异性靶向可塑性和耐药性癌症干细胞亚群。癌细胞具有在不同身份之间切换的能力，这增强了它们增殖和扩散的能力。在这份报告中，我们证明了只有一些癌细胞具有这种特殊的身份转换能力，并且这些细胞可以抵抗目前的癌症治疗。我们开发了一种方法来富集具有这种特殊能力的癌细胞，以便可以在它们身上测试新药，然后使用这种方法来鉴定可以靶向这些细胞的药物。这些危险的细胞必须被根除，以使患者能够长期生存，因此这些是对人类健康的重要发现。
Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/− CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. Cancer stem cell plasticity intersects with EMT to determine therapeutic resistance. Co-treatment with TGFβ and RA enriches a plastic and drug resistant cancer stem cell sub-population for therapeutic testing. Thapsigargin specifically targets the plastic and drug resistant cancer stem cell sub-population. Cancer cells have the ability to switch between different identities that enhance their ability to proliferate and spread. In this report, we demonstrate that only some cancer cells possess this special ability to switch identity, and that these cells can resist current cancer therapies. We develop a method to enrich the cancer cells with this special ability, so that new drugs can be tested on them, and then use this method to identify a drug that can target these cells. These dangerous cells must be eradicated to enable long-term patient survival, and these are therefore significant findings for human health.