Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic
Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic
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DOI：
10.1158/0008-5472.can-06-3946
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发表时间：
2007-05-01
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;Franco, Omar E.;Hayward, Simon W.
本研究探讨了人前列腺癌相关成纤维细胞（CAF）诱导非恶性前列腺上皮细胞（BPH-1）发生肿瘤的机制。CAT表达水平升高的转化生长因子-β 1（TGF-β 1）和基质细胞衍生因子-1（SDF-1/CXCL 12）。TGF-β在体外抑制BPH-1细胞的生长，但被发现是CAF致瘤反应所必需的。这一违反直觉的结果表明TGF-β信号系统参与了与肿瘤发生相关的其他过程。SDF-1受体CXCR 4在良性前列腺组织和培养的BPH-1细胞中以低水平表达。然而，CXCR 4水平在前列腺癌进展期间增加。CXCR 4在BPH 1细胞中被CAF条件培养基和组织重组体中的CAF细胞诱导并定位于细胞膜。TGF-β是必需的，也是足够的，以允许在BPH 1细胞中检测膜定位的CXCR 4。抑制上皮细胞CXCR 4的表达，废除了CAF的致瘤反应。由CAF分泌的SDF-1通过TGF-β调节的CXCR 4激活上皮细胞中的Akt。该机制促进肿瘤发生并消除TGF-β的生长抑制作用。因此，肿瘤间质可通过TGF-β、SDF-1和CXCR 4之间的协同作用促成癌发生。这些实验提示了TGF-β在肿瘤进展过程中可以将其作用从增殖抑制剂转变为增殖促进剂的机制。TGF-β和SDF-1途径都是药物发现工作的目标;这些数据表明这些途径的共同靶向可能有益。
The present study explores the mechanisms by which human prostatic carcinoma-associated fibroblasts (CAF) induce tumorigenesis in initiated but nonmalignant human prostatic epithelial cells (BPH-1). CAT express elevated levels of both transforming growth factor-beta 1 (TGF-beta 1) and stromal cell-derived factor-1 (SDF-1/CXCL12). TGF-beta inhibits the growth of BPH-1 cells in vitro, but was found to be necessary for the tumorigenic response to CAF. This counterintuitive result suggested that the TGF-beta signaling system was involved in other processes relating to tumorigenesis. The SDF-1 receptor, CXCR4, is expressed at low levels in benign prostate tissue and in BPH-1 cells in culture. However, CXCR4 levels increase during prostate cancer progression. CXCR4 was found to be induced and localized to the cell membrane in BPH1 cells by CAF-conditioned medium and by CAF cells in tissue recombinants. TGF-beta was both necessary and sufficient to allow the detection of membrane-localized CXCR4 in BPH1 cells. Suppression of epithelial cell CXCR4 expression abrogated the tumorigenic response to CAF. SDF-1, secreted by CAF, acts via the TGF-beta-regulated CXCR4 to activate Akt in the epithelial cells. This mechanism elicits tumorigenesis and obviates the growth-inhibitory effects of TGF-beta. Thus, tumor stroma can contribute to carcinogenesis through synergism between TGF-beta, SDF-1, and CXCR4. These experiments suggest mechanisms by which TGF-beta can shift its role from an inhibitor to a promoter of proliferation during tumor progression. Both the TGF-beta and SDF-1 pathways are targets of drug discovery efforts; these data suggest potential benefits in the cotargeting of these pathways.