Department of Molecular and Environmental Pathology, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan.
Br J Cancer. 2011 Feb 1;104(3):505-13. doi: 10.1038/sj.bjc.6606070. Epub 2011 Jan 4.
The interaction between prostate cancer cells and osteoblasts is critical for the development of bone metastasis. Metastatic cancer cells may physically contact osteoblasts in the bone microenvironment; however, the biological significance of this interaction is not fully understood.
Human prostate cancer cells (the osteolytic cell line PC-3 and the osteoblastic cell line MDA-PCa 2b) and human osteoblasts (hFOB1.19) were cocultured under two different conditions (bilayer and contact conditions). Differential gene expression profiles of prostate cancer cells were then investigated using microarray analysis. Differentially expressed genes were analysed using RT-PCR and western blotting, and the effect of anti-cadherin neutralising antibodies on their expression was assayed. The osteoclastogenic activity of cells grown under these different conditions was also investigated using an in vitro assay.
When PC-3 or MDA-PCa 2b cells were cocultured with hFOB1.19 cells under contact conditions, the expression of eight genes was upregulated and that of one gene was downregulated in PC-3 cells compared with gene expression in bilayer culture. No differentially expressed genes were detected in MDA-PCa 2b cells. Four of the eight upregulated genes (interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), IL-6 and the third component of complement (C3)) have already been reported to participate in osteoclastogenesis. Indeed, a cell lysate of PC-3 cells grown under contact coculture conditions significantly enhanced osteoclastogenesis in vitro (P<0.005). neutralisation of cadherin-11 with a specific antibody inhibited upregulation of COX-2 and C3 mRNA in PC-3 cells. In contrast, neutralisation of N-cadherin induced upregulation of COX-2 mRNA.
Physical contact between osteolytic prostate cancer cells and osteoblasts may upregulate osteoclastogenesis-related gene expression in prostate cancer cells and enhance osteoclastogenesis. Additionally, cadherin-11 and N-cadherin are involved in this process. These data provide evidence supporting new therapies of prostate cancer bone metastasis that target direct cancer-cell-osteoblast cell-cell contact.
前列腺癌细胞与成骨细胞之间的相互作用对骨转移的发展至关重要。转移性癌细胞可能在骨微环境中与成骨细胞物理接触；然而，这种相互作用的生物学意义尚不完全清楚。
将人前列腺癌细胞（溶骨性细胞系 PC-3 和成骨性细胞系 MDA-PCa2b）与人成骨细胞（hFOB1.19）在两种不同条件（双层和接触条件）下共培养。然后使用微阵列分析研究前列腺癌细胞的差异基因表达谱。使用 RT-PCR 和 Western blot 分析差异表达基因，并检测抗钙黏蛋白中和抗体对其表达的影响。还使用体外测定法研究在这些不同条件下培养的细胞的破骨细胞生成活性。
当 PC-3 或 MDA-PCa2b 细胞与 hFOB1.19 细胞在接触条件下共培养时，与双层培养相比，PC-3 细胞中 8 个基因的表达上调，1 个基因的表达下调。在 MDA-PCa2b 细胞中未检测到差异表达的基因。在 8 个上调基因中，有 4 个（白细胞介素 1β（IL-1β）、环氧化酶 2（COX-2）、IL-6 和补体第三成分（C3））已被报道参与破骨细胞生成。事实上，在接触共培养条件下培养的 PC-3 细胞的细胞裂解物显著增强了体外破骨细胞生成（P<0.005）。用特异性抗体中和钙黏蛋白-11 抑制了 PC-3 细胞中 COX-2 和 C3 mRNA 的上调。相比之下，中和 N-钙黏蛋白诱导了 COX-2 mRNA 的上调。
溶骨性前列腺癌细胞与成骨细胞的物理接触可能上调前列腺癌细胞中与破骨细胞生成相关的基因表达，并增强破骨细胞生成。此外，钙黏蛋白-11 和 N-钙黏蛋白参与了这一过程。这些数据为针对直接癌细胞-成骨细胞细胞间接触的前列腺癌骨转移的新治疗方法提供了证据。
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