Role of TGF-beta in cancer and the potential for therapy and prevention.
Role of TGF-beta in cancer and the potential for therapy and prevention.
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DOI：
10.1586/14737140.4.4.649
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发表时间：
2004-08-01
影响因子：
3.3
通讯作者：
Pasche, Boris
中科院分区：
文献类型：
--
作者：
Kaklamani, Virginia G;Pasche, Boris
转化生长因子（TGF）-β是一种天然存在的细胞生长的有效抑制剂。TGF-β首先结合II型受体（TGFBR 2），然后结合I型受体（TGFBR 1）。TGFBR 1激活导致细胞内信使SMAD磷酸化。由于生长抑制活性降低导致的细胞生长不受限制是TGF-β功能缺陷的最重要特征。越来越多的证据表明，TGF-β途径配体和受体的常见变体改变TGF-β信号传导，从而改变癌症风险。大约14%的普通人群携带TGFBR 1 *6A，这是TGFBR 1基因的一种变体，导致TGF-β介导的生长抑制作用降低。最近的研究表明，TGFBR 1 *6A纯合子和杂合子的总体癌症风险分别增加了70%和19%。这表明TGFBR 1 *6A可能有助于大部分常见癌症的发展，并可能成为癌症化学预防的靶点。虽然TGF-β信号减少会增加癌症风险，但TGF-β分泌和活化的TGF-β信号增强了几种类型肿瘤的侵袭性。活化的TGF-β信号通路正在成为癌症中一个有吸引力的靶点，作者预测，对该通路功能相关变体的评估将导致识别具有较高癌症风险的个体，并解释某些形式的家族性癌症易感性。此外，据预测，TGF-β信号通路的抑制剂将进入癌症临床试验，导致肿瘤进展延迟和总生存期改善。
Transforming growth factor (TGF)-beta is a naturally occurring potent inhibitor of cell growth. TGF-beta binds first to a Type II (TGFBR2), then a Type I receptor (TGFBR1). TGFBR1 activation results in the phosphorylation of intracellular messengers, the SMADs. Unrestricted cell growth due to decreased growth inhibitory activity is a paramount feature of a defect in TGF-beta function. There is growing evidence that common variants of the TGF-beta pathway ligand and receptors that alter TGF-beta signaling modify cancer risk. Approximately 14% of the general population carry TGFBR1*6A, a variant of the TGFBR1 gene that results in decreased TGF-beta-mediated growth inhibition. Recent studies show that overall cancer risk is increased by 70 and 19% among TGFBR1*6A homozygotes and heterozygotes, respectively. This suggests that TGFBR1*6A may contribute to the development of a large proportion of common forms of cancer and may become a target for cancer chemoprevention. While decreased TGF-beta signaling increases cancer risk, TGF-beta secretion and activated TGF-beta signaling enhances the aggressiveness of several types of tumors. The activated TGF-beta signaling pathway is emerging as an attractive target in cancer and the authors predict that assessment of functionally relevant variants of this pathway will lead to the identification of individuals with a higher cancer risk and account for some forms of familial cancer susceptibility. In addition, it is predicted that inhibitors of the TGF-beta signaling pathway will find their way into cancer clinical trials, leading to delays in tumor progression and improvements in overall survival.