The relevance of the TGF-β Paradox to EMT-MET programs.
The relevance of the TGF-β Paradox to EMT-MET programs.
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DOI：
10.1016/j.canlet.2013.02.048
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发表时间：
2013-11-28
期刊：
影响因子：
9.7
通讯作者：
Schiemann, William P.
中科院分区：
文献类型：
--
作者：
Morrison, Chevaun D.;Parvani, Jenny G.;Schiemann, William P.
转化生长因子-β(转化生长因子-β)在肿瘤发生过程中的作用复杂而矛盾，反映了其在正常和早期癌症中作为肿瘤抑制因子的能力，并在晚期肿瘤中具有促癌作用。转化生长因子-β功能的转换被称为“转化生长因子-β悖论”，其表现与癌变过程中上皮-间充质转化程序的启动密切相关。事实上，当癌细胞从转化生长因子-β刺激的EMT计划中出现时，它们很容易显示出各种获得性表型，这些表型为不断增长的癌症提供了选择性优势，包括(I)增强了细胞的迁移和侵袭；(Ii)对细胞毒剂、靶向化疗和放射治疗的抵抗力增强；(Iv)促进了肿瘤转移和疾病复发的启动癌症和干细胞群的扩张。目前，分子，细胞和微环境机制，使后EMT和转移性癌细胞劫持转化生长因子-β的致癌活性仍不完全清楚。此外，对抗EMT程序和限制晚期癌症侵袭性的分子机制，即通过间充质-上皮转化(MET)反应而发生的事件，也需要进一步阐明。在这里，我们回顾了最近的进展，为转化生长因子-β如何促进晚期癌细胞的EMT计划，以及这些事件如何在人类癌症的发展和转移进展中被MET计划平衡提供了新的见解。
The role of transforming growth factor-β (TGF-β) during tumorigenesis complex and paradoxical, reflecting its ability to function as a tumor suppressor in normal and early-stage cancers, and has a tumor promoter in their late-stage counterparts. The switch in TGF-β function is known as the “TGF-β Paradox,” whose manifestations are intimately linked to the initiation of epithelial-mesenchymal transition (EMT) programs in developing and progressing carcinomas. Indeed, as carcinoma cells emerge from EMT programs stimulated by TGF-β, they readily display a variety of acquired phenotypes that provide a selective advantage to growing carcinomas, including (i) enhanced cell migration and invasion; (ii) heightened resistance to cytotoxic agents, targeted chemotherapeutic, and radiation treatments; and (iv) boosted expansion of cancer-initiating and stem-like cell populations that underlie tumor metastasis and disease recurrence. At present, the molecular, cellular, and microenvironmental mechanisms that enable post-EMT and metastatic carcinoma cells to hijack the oncogenic activities of TGF-β remain incompletely understood. Additionally, the molecular mechanisms that counter EMT programs and limit the aggressiveness of late-stage carcinomas, events that transpire via mesenchymal-epithelial transition (MET) reactions, also need to be further elucidated. Here we review recent advances that provide new insights into how TGF-β promotes EMT programs in late-stage carcinoma cells, as well as how these events are balanced by MET programs during the development and metastatic progression of human carcinomas.
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