Laminin和IGF协同介导非肝癌干细胞去分化的机制研究

Cancer stem cells (CSCs) are thought to be responsible for tumor metastasis and recurrence. Recent studies have shown that CSCs might stem from dedifferentiation of differentiated tumor cells in a special microenvironment, yet the conditions and mechanisms of such dedifferentiation have not been elucidated. Based on liver cancer stem cells model we previously established, we took use of Matrigel to simulate the in vivo environment and successfully established a dedifferentiated culture method in vitro. Moreover, we disclosed that Laminin and growth factor IGF, the major component of Matrigel, play a key role in such dedifferentiation process, but the molecular mechanism remains elusive. Summarising our former studies and literatures, we propose that Laminin may act synergistically with IGF to drive the dedifferentiation, which involved in upregulation of Nanog through swapping the activity of Erk1/2 and STAT3. This work is meaningful for understanding the relationship between tumor and microenvironment, uncovering the mechanism of dedifferentiation, providing theoretical basis for making more effective strategy for cancer treatment.

肿瘤干细胞被认为是肿瘤转移和复发的根源，新近研究发现肿瘤干细胞可以来源于特定肿瘤微环境作用下分化型肿瘤细胞的去分化，但目前人们对去分化过程发生的条件及机制尚缺乏深刻认识。我们在前期建立的肝癌干细胞模型基础上，利用Matrigel成功在体外模拟肝癌细胞的去分化现象，并证明其中基质成分Laminin以及生长因子IGF发挥了关键作用，但分子机制不清。结合前期研究和文献，我们提出：肿瘤微环境中Laminin和IGF可通过协同调控Erk1/2与STAT3信号通路间转换，上调Nanog，进而驱动肝癌细胞的去分化。该项研究的顺利实施将拓宽人们对肿瘤干细胞的生物学特征以及与肿瘤微环境间联系的理解和认识，同时将更有助于理清非肝癌干细胞与肝癌干细胞相互转化的条件及机制，为制定更加有效的肿瘤治疗策略提供新的研究思路和理论依据。

肿瘤细胞去分化贯穿肿瘤的起始和演进过程，在肿瘤的发生发展中发挥重要作用。本项目研究发现Laminin可通过整合素受体ITGA3、ITGA6，调控非肝癌干细胞的去分化。而且，在非肝癌干细胞去分化过程中多条信号通路发生了改变，我们研究发现IGF信号通过MEK/ERK/Tcf7l1信号轴增强非肝癌干细胞的自我更新，促进了非肝癌干细胞的去分化作用。另外，结合课题研究，我们还对IGF信号通路调控肝癌细胞耐药性以及急性髓系白血病肿瘤干细胞等进行了拓展性研究。研究结果表明微环境中Laminin及IGF通过多条信号通路调节Nanog的表达，诱导非肝癌干细胞去分化，该研究为靶向肝癌细胞去分化制定有效干预策略提供理论基础。