Transforming growth factor-β promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells
Transforming growth factor-β promotes invasion in tumorigenic but not in nontumorigenic human prostatic epithelial cells
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DOI：
10.1158/0008-5472.can-05-4451
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Hayward, Simon W.
中科院分区：
文献类型：
--
作者：
Ao, Mingfang;Williams, Karin;Hayward, Simon W.
转化生长因子-β（TGF-β）是一种嗜酸性生长因子，其作用取决于环境，包括剂量，靶细胞类型和背景。TGF-β可以引起生长促进和生长抑制活性。在正常组织中，TGF-β通常起到限制生长和维持分化的作用。然而，在肿瘤发生过程中，TGF-β表达和细胞反应的变化可以促进肿瘤发生。本研究探讨了TGF-β对非致瘤性人前列腺上皮细胞系BPH 1和三个衍生的致瘤性亚系BPH 1（CAFTD）1，BPHI（CAFTD）3和BPH 1（CAFTD）5的影响。数据显示，TGF-β对非致瘤细胞和致瘤细胞具有不同的作用。非致瘤细胞的生长受到TGF-β的抑制。相反，致瘤亚系不受生长抑制，而是响应于TGF-β而经历上皮向间充质转化（EMT）。致瘤细胞系显示磷酸化Akt水平组成性升高，其通过阻断Smad 3和p21核转位调节其对TGF-β的反应。在肿瘤发生亚系的TGF-β刺激下，激活的Akt允许细胞逃避细胞周期停滞。磷脂酰肌醇3-激酶/Akt途径也参与TGF-β诱导的EMT，此处定义为诱导波形蛋白表达和增强细胞运动性。在体内，具有组成型活性TGF-β信号传导的致瘤细胞显示EMT的侵袭增加，EMT表达波形蛋白，其特异性地位于肿瘤的侵袭前沿。这些数据表明，恶性转化后，TGF-β可以在促进前列腺癌中发挥直接作用，并且进一步表明这些反应在体内是环境特异性的。
Transforming growth factor-beta (TGF-beta) is a piciotropic growth factor with actions that are dependent on circumstances, including dose, target cell type, and context. TGF-beta can elicit both growth-promoting and growth-suppressive activities. In normal tissues, TGF-beta generally acts to restrict growth and maintain differentiation. However, during tumorigenesis, changes in TGF-beta expression and cellular responses can promote tumorigenesis. The present study examines the effects of TGF-beta on the nontumorigenic human prostatic epithelial cell line BPH1 and on three derivative tumorigenic sublines BPH1(CAFTD)1, BPHI(CAFTD)3, and BPH1(CAFTD)5. The data show that TGF-beta has different effects on the nontumorigenic and tumorigenic cells. The nontumorigenic cells are growth inhibited by TGF-beta. In contrast, the tumorigenic sublines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-beta. The tumorigenic lines show constitutively elevated levels of phosphorylated Akt, which modulates their response to TGF-beta by blocking Smad3 and p21 nuclear translocation. On TGF-beta stimulation of the tumorigenic sublines, the activated Akt allows the cell to escape cell cycle arrest. The phosphatidylinositol 3-kinase/Akt pathway is also involved in TGF-beta-induced EMT, defined here by induction of vimentin expression and enhanced cellular motility. In vivo, tumorigenic cells with constitutively active TGF-beta signaling show increased invasion with EMT, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-beta can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo.