Osteoclasts Are Active in Bone Forming Metastases of Prostate Cancer Patients
Osteoclasts Are Active in Bone Forming Metastases of Prostate Cancer Patients
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DOI：
10.1371/journal.pone.0003627
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发表时间：
2008-11-03
期刊：
影响因子：
3.7
通讯作者：
Ferracini, Riccardo
中科院分区：
文献类型：
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作者：
Roato, Ilaria;D'Amelio, Patrizia;Ferracini, Riccardo
背景：骨形成转移是前列腺癌（CaP）的常见且致残的后果。破骨细胞活性在 CaP 骨转移中的潜在作用尚未完全解释。在本研究中，我们在体外研究了骨形成转移的 CaP 患者是否存在溶骨活性以及如何控制这种活性。方法：纳入了 46 名新诊断的 CaP 患者和健康对照。诊断时，37 名患者仅患有原发性肿瘤，而 9 名患者患有原发性肿瘤并伴有骨形成转移。在所有患者中，没有证据表明转移到其他非骨部位。对于所有患者和对照，我们收集了血液和尿液样本。我们评估了患者的骨稳态；我们进行了外周血单核细胞（PBMC）培养以检测体外破骨细胞生成；我们对参与癌症诱导的破骨细胞形成的分子的血清表达进行剂量调整，例如 RANKL、OPG、TNF-α、DKK-1 和 IL-7。通过实时 PCR，我们定量了显微解剖肿瘤和健康组织切片上的 DKK-1 和 IL-7 基因表达。主要发现：与非骨转移患者和健康对照相比，CaP 骨转移患者表现出骨代谢紊乱，骨吸收和形成增加。 CaP PBMC 培养物显示，由于 RANKL/OPG 比率增加，骨转移患者的破骨细胞生成增强。与对照组相比，我们检测到患者 DKK-1 血清水平和组织基因表达增加。 IL-7在患者血清中结果较高，但其组织基因表达在患者和对照中相当。结论：我们在体外证明破骨细胞生成是骨形成转移癌肿瘤筑巢的活跃机制，并且CaP患者血清DKK-1水平升高，建议深入研究其作为肿瘤标志物的作用。
Background: Bone forming metastases are a common and disabling consequence of prostate cancer (CaP). The potential role of osteoclast activity in CaP bone metastases is not completely explained. In this study, we investigated ex vivo whether the osteolytic activity is present and how it is ruled in CaP patients with bone forming metastases.Methodology: Forty-six patients affected by newly diagnosed CaP and healthy controls were enrolled. At diagnosis, 37 patients had a primary tumour only, while 9 had primary tumour and concomitant bone forming metastases. In all patients there was no evidence of metastasis to other non-bone sites. For all patients and controls we collected blood and urinary samples. We evaluated patients' bone homeostasis; we made peripheral blood mononuclear cell (PBMC) cultures to detect in vitro osteoclastogenesis; we dosed serum expression of molecules involved in cancer induced osteoclatogenesis, such as RANKL, OPG, TNF-alpha, DKK-1 and IL-7. By Real-Time PCR, we quantified DKK-1 and IL-7 gene expression on micro-dissected tumour and healthy tissue sections.Principal Findings: CaP bone metastatic patients showed bone metabolism disruption with increased bone resorption and formation compared to non-bone metastatic patients and healthy controls. The CaP PBMC cultures showed an enhanced osteoclastogenesis in bone metastatic patients, due to an increase of RANKL/OPG ratio. We detected increased DKK-1 serum levels and tissue gene expression in patients compared to controls. IL- 7 resulted high in patients' sera, but its tissue gene expression was comparable in patients and controls.Conclusions: We demonstrated ex vivo that osteoclastogenesis is an active mechanism in tumour nesting of bone forming metastatic cancer and that serum DKK-1 levels are increased in CaP patients, suggesting to deeply investigate its role as tumour marker.