Luo Wen, Shi Qingfeng, Han Mingming, Zhang Zhenwang, Reiter Russel J, Ashrafizadeh Milad, Nabavi Noushin, Sethi Gautam, Nicot Christophe, Mao Ying
Department of Oncology, Suining Central Hospital, Suining, Sichuan, China.
Department of Breast surgery, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
Cytokine Growth Factor Rev. 2025 May 15. doi: 10.1016/j.cytogfr.2025.05.004.
The carcinogenesis and drug resistance can be accelerated by TGF-β, primarily by enhancing epithelial-mesenchymal transition (EMT). This review examines the complex mechanisms by which TGF-β drives EMT across different tumors, highlighting its function in increasing cellular plasticity, promoting metastasis, and contributing to therapy resistance. TGF-β activates both canonical Smad-dependent and non-canonical signaling, leading to profound changes in cell morphology, motility, and stemness. This review highlights recent discoveries on how TGF-β regulates cancer stem cells and contributes to drug resistance, including resistance to both conventional chemotherapy and targeted treatments. In addition, it examines the intricate interaction between TGF-β and the key molecular pathways controlling EMT, such as PI3K/AKT, MAPK, and epigenetic regulators. It also examines potential therapeutic approaches aimed at TGF-β-induced EMT, emphasizing promising preclinical results from novel compounds and combination therapies-including natural products, small-molecule inhibitors, and epigenetic regulators-that interfere with TGF-β receptor activation or downstream signaling pathways. Understanding these complex interactions provides valuable insights for developing more effective cancer therapies. The review concludes by identifying key research gaps as well as suggesting future directions for investigating TGF-β's role in cancer biology and treatment resistance.
转化生长因子-β（TGF-β）可加速肿瘤发生和耐药性，主要是通过增强上皮-间质转化（EMT）来实现。本综述探讨了TGF-β在不同肿瘤中驱动EMT的复杂机制，强调了其在增加细胞可塑性、促进转移以及导致治疗耐药性方面的作用。TGF-β激活经典的Smad依赖信号通路和非经典信号通路，导致细胞形态、运动性和干性发生深刻变化。本综述重点介绍了关于TGF-β如何调节癌症干细胞并导致耐药性的最新发现，包括对传统化疗和靶向治疗的耐药性。此外，还探讨了TGF-β与控制EMT的关键分子途径（如PI3K/AKT、MAPK和表观遗传调节因子）之间的复杂相互作用。还研究了针对TGF-β诱导的EMT的潜在治疗方法，强调了新型化合物和联合疗法（包括天然产物、小分子抑制剂和表观遗传调节因子）的有前景的临床前结果，这些疗法可干扰TGF-β受体激活或下游信号通路。了解这些复杂的相互作用为开发更有效的癌症治疗方法提供了有价值的见解。综述最后确定了关键研究空白，并提出了未来研究TGF-β在癌症生物学和治疗耐药性中作用的方向。
