Leivonen Suvi-Katri, Kähäri Veli-Matti
Department of Dermatology, University of Turku, FI-20521 Turku, Finland.
Int J Cancer. 2007 Nov 15;121(10):2119-24. doi: 10.1002/ijc.23113.
Transforming growth factor-beta (TGF-beta) family members are polypeptides with dual tumor suppressive and oncogenic effects. They signal through serine/threonine kinase receptor complexes, which phosphorylate cytoplasmic mediators, the Smads. Upon phosphorylation, Smads translocate to the nucleus and associate with transcriptional coactivators or corepressors, and regulate the transcriptional activation of various TGF-beta responsive genes. In addition, TGF-beta activates cellular mitogen-activated protein kinase signaling pathways, which crosstalk with Smad signaling and regulate growth, survival and motility of cells. During tumorigenesis, malignantly transformed cells often lose the response to the tumor suppressive effects of TGF-beta, which, in turn, starts to act as an autocrine tumor promoting factor by enhancing cancer invasion and metastasis. In this review, we summarize current view on the role of TGF-beta signaling in tumorigenesis, with emphasis on cancer invasion and metastasis. On the basis of these recent observations, we discuss new therapeutic strategies targeting TGF-beta signaling at distinct levels as a basis for inhibiting tumor growth, angiogenesis, invasion and metastasis.
转化生长因子-β（TGF-β）家族成员是具有双重肿瘤抑制和致癌作用的多肽。它们通过丝氨酸/苏氨酸激酶受体复合物发出信号，该复合物使细胞质介质Smads磷酸化。磷酸化后，Smads易位至细胞核并与转录共激活因子或共抑制因子结合，从而调节各种TGF-β反应性基因的转录激活。此外，TGF-β激活细胞丝裂原活化蛋白激酶信号通路，该通路与Smad信号相互作用并调节细胞的生长、存活和运动。在肿瘤发生过程中，恶性转化细胞常常失去对TGF-β肿瘤抑制作用的反应，而TGF-β反过来通过增强癌症侵袭和转移开始作为自分泌肿瘤促进因子发挥作用。在本综述中，我们总结了目前关于TGF-β信号在肿瘤发生中的作用的观点，重点是癌症侵袭和转移。基于这些最新观察结果，我们讨论了针对TGF-β信号在不同水平的新治疗策略，作为抑制肿瘤生长、血管生成、侵袭和转移的基础。
