肿瘤干细胞自我更新的分子调控机制及其对癌症生物学特性的影响

The cancer stem cell theory for oncogenesis，since its inception, has been at the forefront of cancer research for the past 18 years. There are few studies that have demonstrated the ability of a small population of cancer cells within the bulk of a tumor, upon isolation can undergo a low rate of asymmetrical cell division – the hallmark of normal stem cells. However, mechanisms that regulate the self-reprogramming of cancer stem cells remain largely unknown. This application focuses on two important questions: (1) under malignant transformation, what are the mechanisms that regulate the switch between the asymmetrical division and the symmetrical division which may differ from that of the normal stem cells? (2) whether the symmetrically dividing cells (SD cells) and the asymmetrically divided cells (ASD ells) possess different cancer biology characteristics? The strength of this application is that it combines the forefront of cancer research (the cancer stem cell theory) with the forefront of stem cell research (regulatory mechanisms underlying the symmetrical and asymmetrical division), with the urgency to establish stable cellular models of the two types of stem cell division, with the development of animal models of cancer in an intact host in which the cancer biological properties of the SD- and ASD-cells can be evaluated, and with the in vivo imaging techniques that afford real-time visualization. This comprehensive approach will allow us to illustrate the “stemness” under malignancy that allows cancer cells to exploit the mechanism of asymmetrical division for self-renewal at the cellular, molecular and the whole organism level. This application is innovative both mechanistically and technically. It will foster new insights on the cancer stem cell theory and will have significant implications for future clinical translation.

肿瘤干细胞致癌假说的提出，开辟了癌症研究领域的新前沿。然而由于稳定的肿瘤干细胞非对称分裂的模型缺乏，肿瘤干细胞利用这一分裂方式进行自我更新的调控机制尚未知。本项目聚焦两个未解决的科学问题：（1）在癌变的环境下，调控肿瘤干细胞对称与非对称分裂转换的分子机制是什么?（2)对称分裂和非对称分裂的肿瘤细胞是否有着不同的癌症生物学特性? 该项目具体科学问题的立项集结了癌症生物学的前沿（肿瘤干细胞致癌假说）、干细胞领域的前沿（对称与非对称分裂的分子调控）、稳定肿瘤干细胞模型的创建（对称和非对称肿瘤干细胞模型）、评估肿瘤干细胞癌症生物学特性的动物实验模型的建立、以及活细胞和活体荧光分子影像技术，从分子、细胞和肿瘤整体的不同层面，来阐明在癌变环境下，肿瘤干细胞利用非对称分裂进行自我更新的"干性"机制。此项研究富有科学创意和技术创新，将为“干细胞致癌假说”提供更深入的理论和新的实验的依据，有着深远的临床转化

肿瘤干细胞理论认为癌症是一种干细胞疾病，肿瘤的进展、复发和转移或多或少均有肿瘤干细胞的参与。我们的前期临床和基础研究展示了肿瘤干细胞的对称和非对称分裂对肿瘤的进展具有重要作用。然而由于稳定的肿瘤干细胞非对称分裂的模型缺乏，肿瘤干细胞利用这一分裂方式进行自我更新的调控机制尚未知。我们首次显示了肿瘤干细胞对称与非对称的自我更新方式能够对肿瘤发生发展产生深远影响。研究内容：本项目的研究主要目标就是探讨对称分裂和非对称分裂的肿瘤细胞不同的癌症生物学特性，进而更深入的揭示在癌变的环境下，调控肿瘤干细胞对称与非对称分裂转换的分子和生理机制。主要研究内容：(1)探讨对称和非对称分裂的两种细胞的生物学特性差异以及对保持干性的影响；（2）Nr5a2多能干性基因参与调控肺腺癌干细胞的自我更新的机制研究；（3）CDH1参与调控肺腺癌干细胞的自我更新的机制研究。重要结果：（1）对称和非对称分裂的两种细胞的生物学特性具有明显的差异，干性相关基因在两种细胞中存在差异表达。（2）通过构建稳定的敲低和过表达Nr5a2细胞株，我们发现Nr5a2可以通过转录上调Nanog诱导肺肿瘤干细胞特性，促进肿瘤发生和进展。（3）使用LLC-SD模型中,我们揭示了在致癌途径和干细胞途径之间的复杂的交叉作用，其中Cdh1作为致癌基因，通过激活磷酸肌醇3-激酶(PI3K)和抑制丝裂原活化蛋白激酶(MAPK)途径促进肺肿瘤干细胞更新。科学意义：通过这一研究，我们期待在后继研究中筛选不同生物学性状的干细胞的特异性临床标志和筛选阻断肿瘤干细胞向后期演化的靶标，这将对及早发现高风险患者和正确预测肿瘤发展方向具有重要的临床意义，更多的患者将从针对肿瘤干细胞的治疗中获益。

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