Metastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are characterized as limiting steps for metastasis. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are opposite dynamic multistep processes that enable these critical events in metastasis by altering the phenotype of cancer cells and improving their ability to migrate, invade and seed at distant organs. Among the molecular pathways that promote tumorigenesis in late-stage cancers, transforming growth factor-β (TGF-β) is described as an EMT master inducer by controlling different genes and proteins related to cytoskeleton assembly, cell-cell attachment and extracellular matrix remodeling. Still, despite the successful outcomes of different TGF-β pharmacological inhibitors in cell culture (in vitro) and animal models (in vivo), results in cancer clinical trials are poor or inconsistent at least, highlighting the existence of crucial components in human cancers that have not been properly explored. Here we review most recent findings to provide perspectives bridging the gap between on-target anti-TGF-β therapies in vitro and in pre-clinical models and the poor clinical outcomes in treating cancer patients. Specifically, we focus on (i) the dual roles of TGF-β signaling in cancer metastasis; (ii) dynamic signaling; (iii) functional differences of TGF-β free in solution vs. in exosomes; (iv) the regulatory effects of tumor microenvironment (TME) – particularly by cancer-associated fibroblasts – on TGF-β signaling pathway. Clearly identifying and establishing those missing links may provide strategies to revitalize and clinically improve the efficacy of TGF-β targeted therapies.

转移是癌症患者死亡的主要原因。在癌症进展过程中，细胞从原发肿瘤中的最初分离以及随后第二器官的定植被表征为转移的限制步骤。上皮-间质转化（EMT）和间质-上皮转化（MET）是相反的动态多步过程，这些过程通过改变癌细胞的表型并提高其在远处器官的迁移，侵袭和繁殖的能力而使这些关键事件发生在转移中。在晚期癌症中促进肿瘤发生的分子途径中，转化生长因子-β（TGF-β）被描述为通过控制与细胞骨架组装，细胞-细胞附着和细胞外基质重塑有关的不同基因和蛋白质而成为EMT主诱导剂。仍然，体外）和动物模型（体内），癌症临床试验的结果至少很差或不一致，这突出表明了人类癌症中关键要素的存在，而这些要素尚未得到适当的探索。在这里，我们回顾了最新的发现，以期弥合目标抗TGF-β治疗之间的差距体外以及临床前模型和治疗癌症患者的不良临床结果。具体而言，我们专注于（i）TGF-β信号传导在癌症转移中的双重作用；（ii）动态信令；（iii）溶液中游离TGF-β与外来体中游离TGF-β的功能差异；（iv）肿瘤微环境（TME），特别是癌症相关的成纤维细胞，对TGF-β信号通路的调节作用。清楚地确定并建立那些缺失的联系可能会为振兴TGF-β靶向疗法并在临床上提高疗效提供战略。