Xu Chang, Graf Lynn F, Fazli Ladan, Coleman Ilsa M, Mauldin Denise E, Li Danbin, Nelson Peter S, Gleave Martin, Plymate Stephen R, Cox Michael E, Torok-Storb Beverly J, Knudsen Beatrice S
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Prostate. 2007 Nov 1;67(15):1621-9. doi: 10.1002/pros.20655.
Prostate cancer frequently metastasizes to bone. Androgen suppression treatment is initially highly effective, but eventually results in resistant cancer cells. This study evaluates the effects of androgen suppression on the bone and bone marrow (BM). In particular we questioned whether the androgen therapy could adversely facilitate prostate cancer progression through an increase growth factor secretion by the bone microenvironment.
Global gene expression is analyzed on mPEDB DNA microarrays. Insulin-like growth factor binding protein-5 (IGFBP5) is detected by immunohistochemistry in mouse tissues and its regulation measured by qPCR and Western blotting in human BM stromal cells. Effects of extracellular matrix-associated IGFBP5 on human prostate epithelial cells are tested in an MTS cell-growth assay.
Castration increases expression of 159 genes (including 4 secreted cytokines) and suppresses expression of 84 genes. IGFBP5 is most consistently increased and the increase in expression is reversed by testosterone administration. IGFBP5 protein is detected in vivo in osteoblasts, BM stromal cells, and endothelial cells. Primary human stromal cell cultures secrete IGFBP5. In vitro, treatment of immortalized human marrow stromal cells with charcoal-stripped serum increases IGFBP5 mRNA expression, which is reversed by androgen supplementation. IGFBP5 is incorporated into the extracellular matrix. Further, IGFBP5 immobilized on extracellular matrices of stromal cells enhances the growth of immortalized prostate epithelial cells.
Androgen suppressive therapy increases IGFBP5 in the BM microenvironment and thereby may facilitate the progression of prostate cancer.
前列腺癌常转移至骨骼。雄激素抑制治疗起初非常有效，但最终会导致癌细胞产生耐药性。本研究评估雄激素抑制对骨骼和骨髓（BM）的影响。我们特别质疑雄激素治疗是否会通过增加骨微环境中生长因子的分泌而对前列腺癌进展产生不利影响。
在mPEDB DNA微阵列上分析整体基因表达。通过免疫组织化学在小鼠组织中检测胰岛素样生长因子结合蛋白5（IGFBP5），并通过定量聚合酶链反应（qPCR）和蛋白质免疫印迹法在人骨髓基质细胞中测量其调控情况。在MTS细胞生长试验中测试细胞外基质相关的IGFBP5对人前列腺上皮细胞的影响。
去势增加了159个基因的表达（包括4种分泌的细胞因子）并抑制了84个基因的表达。IGFBP5的表达增加最为一致，且睾酮给药可逆转其表达增加。在体内，成骨细胞、骨髓基质细胞和内皮细胞中可检测到IGFBP5蛋白。原代人基质细胞培养物分泌IGFBP5。在体外，用活性炭处理的血清处理永生化人骨髓基质细胞可增加IGFBP5 mRNA表达，而雄激素补充可逆转这一现象。IGFBP5整合到细胞外基质中。此外，固定在基质细胞外基质上的IGFBP5可增强永生化前列腺上皮细胞的生长。
雄激素抑制治疗可增加骨髓微环境中的IGFBP5，从而可能促进前列腺癌的进展。
