Ao Mingfang, Franco Omar E, Park Dean, Raman Dayanidhi, Williams Karin, Hayward Simon W
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Cancer Res. 2007 May 1;67(9):4244-53. doi: 10.1158/0008-5472.CAN-06-3946.
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). CAF express elevated levels of both transforming growth factor-beta1 (TGF-beta1) 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.
本研究探讨了人前列腺癌相关成纤维细胞（CAF）在起始但非恶性的人前列腺上皮细胞（BPH-1）中诱导肿瘤发生的机制。CAF中转化生长因子-β1（TGF-β1）和基质细胞衍生因子-1（SDF-1/CXCL12）的表达水平均升高。TGF-β在体外抑制BPH-1细胞的生长，但被发现是对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CXCR4在良性前列腺组织和培养的BPH-1细胞中低水平表达。然而，CXCR4水平在前列腺癌进展过程中升高。在组织重组体中，发现CAF条件培养基和CAF细胞可诱导BPH1细胞中的CXCR4并使其定位于细胞膜。TGF-β对于在BPH1细胞中检测膜定位的CXCR4既是必需的也是充分的。上皮细胞CXCR4表达的抑制消除了对CAF的致瘤反应。CAF分泌的SDF-1通过TGF-β调节的CXCR4作用于上皮细胞，激活Akt。这种机制引发肿瘤发生，并消除了TGF-β的生长抑制作用。因此，肿瘤基质可通过TGF-β、SDF-1和CXCR4之间的协同作用促进癌变。这些实验提示了TGF-β在肿瘤进展过程中如何从增殖抑制剂转变为增殖促进剂的机制。TGF-β和SDF-1途径都是药物研发的靶点；这些数据表明同时靶向这些途径可能具有益处。
