Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.
Cancer Res. 2019 Aug 1;79(15):3797-3805. doi: 10.1158/0008-5472.CAN-18-2019. Epub 2019 Jul 12.
The TGFβ cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFβ signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFβ signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFβ responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPβ, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFβ responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.
TGFβ 细胞因子在肿瘤进展过程中起着双重作用。在正常和癌前癌细胞中，TGFβ 信号通路抑制增殖，促进细胞周期停滞和细胞凋亡。然而，该通路在晚期癌细胞中的激活可以促进上皮-间充质转化、干细胞特性和迁移特性，从而增强肿瘤发生和转移。TGFβ 信号在肿瘤进展过程中的相反功能使其成为开发抗癌干预措施的具有挑战性的目标。然而，最近发现细胞上下文决定因素，特别是转录调节剂 Smads 的结合伴侣，对于将 TGFβ 反应从促凋亡切换为促转移至关重要。在这篇综述中，我们总结了最近发现的上下文决定因素（如 PSPC1、KLF5、14-3-3ζ、C/EBPβ 等）以及肿瘤细胞如何管理上下文依赖性自主 TGFβ 反应以增强肿瘤进展的机制。随着一些上下文决定因素及其效应物在肿瘤进展过程中的改变表达，异常的分子促转移开关可能成为开发抗癌策略的一类新的治疗靶标。
