Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.
Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.
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发表时间：
2003-07
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通讯作者：
K. Fizazi;Jun Yang;S. Peleg;C. Sikes;E. Kreimann;D. Daliani;M. Olivé;Kevin A. Raymond;T. Janus
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作者：
K. Fizazi;Jun Yang;S. Peleg;C. Sikes;E. Kreimann;D. Daliani;M. Olivé;Kevin A. Raymond;T. Janus
前列腺癌特异性转移到骨，并导致骨形成。我们以前报道，共培养MDA PCa 2b前列腺癌细胞与原代小鼠成骨细胞（PMO）诱导PMO增殖和分化。在严重联合免疫缺陷病小鼠的骨中注射MDA PCa 2b细胞后，在体内也观察到成骨细胞反应。本研究的目的是确定导致体内成骨细胞病变的事件序列，并使用该体外模型，确定前列腺癌成骨细胞骨转移病理生理学中各种基因和细胞通路的贡献。实验设计和结果我们在严重联合免疫缺陷病小鼠的骨中注射MDA PCa 2b细胞后早在2周就显示了从头骨形成的组织学证据。在体外，我们表明，PMO诱导MDA PCa 2b增殖，这表明这些细胞和PMO之间的协同旁分泌回路。内皮素（ET）-1是几种细胞类型的促分裂剂，由所有测试的前列腺癌细胞系产生，并且阿曲生坦（Atrasentan），ET-1受体A的拮抗剂，部分逆转MDA PCa 2b细胞诱导的PMO增殖。已知ET-1与许多生长因子，包括胰岛素样生长因子（IGF）-I共致。在这项研究中，我们报告说，IGF结合蛋白（IGFBP）-3转录（调节游离IGF的水平）下调与PMO共培养的前列腺癌细胞，而前列腺特异性抗原（蛋白酶已知切割IGFBP-3）检测在150-400 ng/ml的范围。因此，IGFBP-3在PMO中具有抗增殖作用，其在我们的体外系统中减弱。综上所述，我们的研究还暗示IGF轴在这种骨转移模型中发挥作用。其次，在与PMO一起生长的前列腺癌细胞中，小鼠双分钟2（一种调节p53的蛋白质）的转录水平增加。小鼠双微体2的p53依赖性和非依赖性致癌活性表明成骨细胞诱导前列腺癌细胞的存活优势。最后，我们发现，在MDA PCa 2b细胞存在下培养的PMO中，骨保护素的表达降低，核因子-κ B配体的受体激活剂的表达增加，这两个事件与破骨细胞活化和骨吸收相关。结论：我们的研究结果提供了证据表明，影响骨形成和骨吸收的多种不同的分子事件与前列腺癌骨转移的骨量增加一致。这些数据也为开发针对这些分子变化的治疗策略提供了理论基础。
PURPOSE Prostate cancer specifically metastasizes to bone where it leads to bone formation. We previously reported that coculturing MDA PCa 2b prostate cancer cells with primary mouse osteoblasts (PMOs) induced PMO proliferation and differentiation. An osteoblastic reaction was also observed in vivo after injection of MDA PCa 2b cells into the bones of severe combined immunodeficient disease mice. The aim of this study was to identify the sequence of events that leads to these osteoblastic lesions in vivo and, using this in vitro model, to define the contributions of various genes and cellular pathways in the pathophysiology of osteoblastic bone metastases of prostate cancer. EXPERIMENTAL DESIGN AND RESULTS We show histological evidence of de novo bone formation as early as 2 weeks after injection of MDA PCa 2b cells in the bone of severe combined immunodeficient disease mice. In vitro, we show that PMOs induce MDA PCa 2b proliferation, suggesting a synergistic paracrine loop between these cells and PMOs. Endothelin (ET)-1, which is a mitogen for several cell types, is produced by all prostate cancer cell lines tested, and Atrasentan, an antagonist of ET-1 receptor A, partially reversed PMO proliferation induced by MDA PCa 2b cells. ET-1 is known to be comitogenic with a number of growth factors, including insulin-like growth factor (IGF)-I. In this study, we report that IGF-binding protein (IGFBP)-3 transcripts (that regulate levels of free IGF) are down-regulated in prostate cancer cells cocultured with PMO, whereas prostate-specific antigen (a protease known to cleave IGFBP-3) is detected in the 150-400 ng/ml range. Accordingly, IGFBP-3 has antiproliferative effects in PMOs, which were attenuated in our in vitro system. Taken together, our studies also implicate the IGF axis to play a role in this model of bone metastases. Secondly, the transcript level of mouse double minute 2 (a protein that regulate p53) was increased in prostate cancer cells grown with PMOs. The p53-dependent and -independent oncogenic activities of mouse double minute 2 suggest that osteoblasts induce a survival advantage in prostate cancer cells. Lastly, we show that expression of osteoprotegerin is decreased and of receptor activator of nuclear factor-kappaB ligand is increased in PMOs cultured in the presence of MDA PCa 2b cells, two events associated with osteoclast activation and bone resorption. CONCLUSIONS Our results provide evidence that multiple and distinct molecular events affecting both bone formation and bone resorption concur to the increase bone mass in prostate cancer bone metastases. These data also provide a rationale for developing therapeutic strategies designed to target these molecular changes.