Department of Molecular Biology, Princeton University, Princeton, NJ, United States.
Eur J Cancer. 2010 May;46(7):1232-40. doi: 10.1016/j.ejca.2010.02.040. Epub 2010 Mar 20.
Transforming growth factor (TGF)-beta signalling plays a dichotomous role in tumour progression, acting as a tumour suppressor early and as a pro-metastatic pathway in late-stages. There is accumulating evidence that advanced-stage tumours produce excessive levels of TGF-beta, which acts to promote tumour growth, invasion and colonisation of secondary organs. In light of the pro-metastasis function, many strategies are currently being explored to antagonise the TGF-beta pathway as a treatment for metastatic cancers. Strategies such as using large molecule ligand traps, reducing the translational efficiency of TGF-beta ligands using antisense technology, and antagonising TGF-beta receptor I/II kinase function using small molecule inhibitors are the most prominent methods being explored today. Administration of anti-TGF-beta therapies alone, or in combination with immunosuppressive or cytotoxic therapies, has yielded promising results in the preclinical and clinical settings. Despite these successes, the temporal- and context-dependent roles of TGF-beta signalling in cancer has made it challenging to define patient subgroups that are most likely to respond, and the therapeutic regimens that will be most effective in the clinic. Novel mouse models and diagnostic tools are being developed today to circumvent these issues, which may potentially expedite anti-TGF-beta drug development and clinical application.
转化生长因子-β（TGF-β）信号在肿瘤进展中起着双重作用，早期作为肿瘤抑制因子，晚期作为促转移途径。越来越多的证据表明，晚期肿瘤产生过多的 TGF-β，其作用是促进肿瘤生长、侵袭和转移到次级器官。鉴于促转移功能，目前正在探索许多策略来拮抗 TGF-β 途径作为转移性癌症的治疗方法。目前最突出的方法是使用大分子配体陷阱、使用反义技术降低 TGF-β配体的翻译效率，以及使用小分子抑制剂拮抗 TGF-β 受体 I/II 激酶功能。单独或联合免疫抑制或细胞毒性治疗应用抗 TGF-β 疗法在临床前和临床环境中都取得了有希望的结果。尽管取得了这些成功，但 TGF-β 信号在癌症中的时间和上下文依赖性作用使得定义最有可能响应的患者亚组以及在临床中最有效的治疗方案变得具有挑战性。目前正在开发新的小鼠模型和诊断工具来规避这些问题，这可能会加速抗 TGF-β 药物的开发和临床应用。
