Zheng Yu, Basel Dennis, Chow Shu-Oi, Fong-Yee Colette, Kim Sarah, Buttgereit Frank, Dunstan Colin R, Zhou Hong, Seibel Markus J
Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, NSW, 2139, Australia,
Clin Exp Metastasis. 2014 Dec;31(8):921-33. doi: 10.1007/s10585-014-9680-3. Epub 2014 Sep 16.
In prostate cancer metastases to bone, cancer cell-derived cytokines stimulate RANKL expression by cells of the osteoblast lineage, which in turn activates osteoclastic bone resorption. However, it is unclear whether cells of the osteoblast lineage signal back to prostate cancer cells, and if so, whether such direct cross-talk can be targeted therapeutically. Using the human prostate cancer cell line, PC3, we identified two novel signalling pathways acting between cells of the osteoblast lineage and cancer cells. First, exposure to RANKL stimulated the expression and release of IL-6 by PC3 cells in vitro (which is known to promote RANKL expression by osteoblasts). Second, treatment of PC3 cells with IL-6 increased the expression of RANK, the cognate receptor of RANKL, and enhanced the RANKL-induced release of IL-6 by PC3 cells. Third, targeted disruption of IL-6 signaling with tocilizumab, a clinically available antibody against the human IL-6 receptor, inhibited skeletal tumor growth in vivo and reduced serum RANKL levels as well as RANK expression by PC3-derived bone tumors. Similar effects were achieved when RANK expression was knocked down in PC3 cells. In contrast, disruption of IL-6 or RANK/RANKL signalling had no effect on PC3 tumor growth in soft tissues, indicating that these signalling pathways act specifically within the bone microenvironment. In conclusion, prostate cancer cells and cells of the osteoblast lineage communicate via two inter-dependent signaling pathways, which through auto-amplification strongly enhance metastatic prostate cancer growth in bone. Both pathways may be targeted for effective therapeutic intervention.
在前列腺癌骨转移过程中，癌细胞衍生的细胞因子刺激成骨细胞谱系细胞表达RANKL，进而激活破骨细胞的骨吸收。然而，尚不清楚成骨细胞谱系细胞是否会反向作用于前列腺癌细胞，如果存在这种反向作用，那么这种直接的相互作用是否能够成为治疗靶点。我们使用人前列腺癌细胞系PC3，确定了成骨细胞谱系细胞与癌细胞之间存在的两条新的信号通路。首先，体外实验中，PC3细胞暴露于RANKL后可刺激其表达和释放IL-6（已知IL-6可促进成骨细胞表达RANKL）。其次，用IL-6处理PC3细胞可增加RANKL同源受体RANK的表达，并增强RANKL诱导的PC3细胞释放IL-6。第三，使用临床上可用的抗人IL-6受体抗体托珠单抗靶向阻断IL-6信号，可抑制体内骨肿瘤生长，并降低血清RANKL水平以及PC3来源的骨肿瘤中的RANK表达。在PC3细胞中敲低RANK表达也能产生类似效果。相反，阻断IL-6或RANK/RANKL信号对PC3细胞在软组织中的肿瘤生长没有影响，这表明这些信号通路在骨微环境中具有特异性作用。总之，前列腺癌细胞和成骨细胞谱系细胞通过两条相互依赖的信号通路进行通讯，这两条通路通过自身放大作用强烈促进转移性前列腺癌在骨中的生长。这两条通路都可能成为有效的治疗干预靶点。
