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Cancer Res:清华大学郭伟课题组揭示临床肺肿瘤干细胞的自我更新与耐药机制

2017-04-28 15:35  
内容快照:

2017年4月17日,国际著名肿瘤学杂志《Cancer Research》上在线发表了清华大学医学院郭伟课题组题为《NOTCH1 signaling regulates self-renewal and platinum chemoresistance of cancer stem-like cells in human non-small cell lung cancer》(NOTCH1信号通路调控非小细胞肺肿瘤干细胞的自我更新与耐药)的研究文章。南京医科大学联合培养张赟博士、清华医学院博士生徐伟、协和医院郭慧琴教授是文章的共同第一作者。

研究建立了原创的临床肿瘤研究技术(patient-derived Cells and xenograft models),分离出新颖的肺肿瘤干细胞、并揭示了这些细胞自我更新与化疗耐药的机制。基于发现,提出了新的解决肺癌化疗耐药的治疗策略。肿瘤干细胞被认为是肿瘤发生、转移、耐药和复发的关键根源之一。以上新技术和发现是对精准医疗的重要贡献。

Cancer Res:清华大学郭伟课题组揭示临床肺肿瘤干细胞的自我更新与耐药机制

原文链接:

NOTCH1 signaling regulates self-renewal and platinum chemoresistance of cancer stem-like cells in human non-small cell lung cancer

原文摘要:

Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse and therapeutic resistance, but their specific pathogenic characters in many cancers including non-small cell lung cancer (NSCLC) have yet to be well defined. Here we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166+CD49fhiCD104-Lin- LCSC present in all human specimens of NSCLC examined, regardless of their histological subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a γ-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo. Overall, our results define the pathogenic characters of a cancer stem-like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease.

DOI:10.1158/0008-5472.CAN-16-1633

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