TGF-β促进状细胞癌的异质性和耐药性
Naoki Oshimori1, Daniel Oristian1, Elaine Fuchs2
1Robin Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|February 28, 2015
概括
转化生长因子-β (TGF-β) 通过涉及p21和NRF2的非遗传机制驱动状细胞癌干细胞 (SCC-SCs) 的瘤异质性和耐药性,影响癌症治疗的有效性.
科学领域:
- 在瘤学瘤学.
- 癌症干细胞生物学
- 分子信号传输的方法
背景情况:
- 长寿的癌症干细胞逃避治疗,导致瘤复发.
- 产生瘤异质性和耐药性的机制仍然不完全理解.
研究的目的:
- 研究转化生长因子-β (TGF-β) 在推动状细胞癌干细胞 (SCC-SCs) 异质性和耐药性的作用.
- 阐明SCC-SC中受TGF-β影响的信号通路和细胞行为.
主要方法:
- 在SCC-SCs中开发一个功能性报告系统,用于谱系追踪和TGF-β信号的基因废除.
- 分析TGF-β信号梯度在瘤-肌瘤界面的分析.
- 评估TGF-β响应和不响应的SCC-SC中的细胞循环特性,入侵,分化和药物敏感性.
- 研究分子机制,包括p21和NRF2稳定,以及谷氨代谢.
主要成果:
- 在瘤-肌瘤界面的TGF-β信号异质性促进了邻近的SCC-SCs中较慢的循环.
- 响应TGF-β的SCC-SCs表现出增加的入侵,异常分化,以及对抗癌药物的增强抵抗力.
- TGF-β上调调节p21,从而稳定NRF2,导致谷氨代谢增加和降低药物的疗效.
- 更慢的细胞循环本身不会产生耐药性;TGF-β诱导的分子通路至关重要.
结论:
- TGF-β信号建立了一个非遗传机制,驱动SCC-SC中的异质性和耐药性.
- 向TGF-β/p21/NRF2轴可以克服状细胞癌中的耐药性.
- 了解这些途径对于开发更有效的癌症疗法至关重要.
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