Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic

被引:217
作者
Ao, Mingfang
Franco, Omar E.
Park, Dean
Raman, Dayanidhi
Williams, Karin
Hayward, Simon W.
机构
[1] Vanderbilt Univ, Med Ctr, Dept Urol Surg, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Div Hematol & Oncol, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA
关键词
D O I
10.1158/0008-5472.CAN-06-3946
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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收藏
页码:4244 / 4253
页数:10
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