Center of Biomechanics and Skeletal Biology, Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany.
Bone. 2010 Feb;46(2):524-33. doi: 10.1016/j.bone.2009.09.024. Epub 2009 Sep 29.
Prostate cancer primarily metastasizes to bone, and the interaction of cancer cells with bone cells results in a local activation of bone formation and/or bone resorption. Since the cellular and molecular mechanisms underlying the development of these tumor-induced osteoblastic or osteolytic lesions are still poorly understood, we have compared the effects of two prostate cancer cell lines, osteoblastic MDA-PCa-2b cells and osteolytic PC-3 cells, on bone-forming osteoblasts. Using Affymetrix Gene Chip hybridization followed by qRT-PCR confirmation we were able to identify specific genes, including Smpd3 and Dmp1, whose expression is significantly reduced upon treatment with PC-3-conditioned medium. Moreover, we observed that PC-3-conditioned medium led to a marked induction of several cytokine genes, including Cxcl5, Cxcl12 and Tnfsf11, the latter one encoding for the osteoclast differentiation factor Rankl. Likewise, when we analyzed the effects of MDA-PCa-2b- and PC-3-conditioned medium on signal transduction in osteoblasts we did not only observe opposite effects on the canonical Wnt signalling pathway, but also a specific induction of Erk and Stat phosphorylation by PC-3-conditioned medium. Most importantly, the induction of Cxcl5, Cxcl12 and Tnfsf11 in osteoblasts by PC-3-conditioned medium was abrogated by the Stat3/5 inhibitor piceatannol, whereas the selective blockade of Stat1 and Erk activation had no effect. Together with the finding, that activated Stat3 in osteoblasts was detectable in bone biopsies from patients with osteolytic metastases, our data suggest that the Stat3/5-dependent activation of cytokine expression in osteoblasts may have a significant impact on cancer cell migration and proliferation, but also on osteoclast activation.
前列腺癌主要转移到骨骼，癌细胞与骨细胞的相互作用导致局部骨形成和/或骨吸收的激活。由于这些肿瘤诱导的成骨或溶骨性病变发展的细胞和分子机制仍知之甚少，我们比较了两种前列腺癌细胞系，成骨性 MDA-PCa-2b 细胞和溶骨性 PC-3 细胞，对成骨细胞的影响。使用 Affymetrix Gene Chip 杂交，然后通过 qRT-PCR 确认，我们能够鉴定出特定的基因，包括 Smpd3 和 Dmp1，其表达在 PC-3 条件培养基处理后显著降低。此外，我们观察到 PC-3 条件培养基导致几种细胞因子基因的显著诱导，包括 Cxcl5、Cxcl12 和 Tnfsf11，后者编码破骨细胞分化因子 Rankl。同样，当我们分析 MDA-PCa-2b-和 PC-3 条件培养基对成骨细胞信号转导的影响时，我们不仅观察到对经典 Wnt 信号通路的相反作用，而且还观察到 PC-3 条件培养基特异性诱导 Erk 和 Stat 磷酸化。最重要的是，PC-3 条件培养基诱导成骨细胞中 Cxcl5、Cxcl12 和 Tnfsf11 的表达被 Stat3/5 抑制剂 piceatannol 阻断，而选择性阻断 Stat1 和 Erk 激活则没有作用。结合在溶骨性转移患者的骨活检中可检测到激活的 Stat3 在成骨细胞中的发现，我们的数据表明，Stat3/5 依赖性的细胞因子表达激活可能对癌细胞迁移和增殖产生重大影响，但也对破骨细胞激活有影响。
