Trinkaus Mateya, Ooi Wei Seong, Amir Ethan, Popovic Snezana, Kalina Marion, Kahn Hariette, Singh Gurmit, Gainford Mary Corona, Clemons Mark
Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
Oncol Rep. 2009 May;21(5):1153-9. doi: 10.3892/or_00000335.
The benefits of bisphosphonates (BPs) in reducing skeletal-related events (SREs) in patients with bone metastases has mainly been attributed to their potent osteoclast inhibiting effect. However, despite the use of modern systemic anticancer therapy including potent BPs, many patients with bone metastases continue to have SREs. An improved understanding of the fundamental mechanisms of bone destruction allows for further development of appropriate targeted treatments. In this study, archival paraffin-embedded bone metastases specimens from patients with metastatic breast cancer were examined for the presence of osteoclasts, expression of the receptor activator of nuclear factor kappaB (RANK), RANK Ligand (RANKL), osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF). Histological specimens were available for primary breast cancer, lymph node metastases, normal breast and normal bone tissues for comparison. Bone metastasis specimens were available for 20 BP naïve patients and two BP-treated patients. Osteoclasts were significantly increased in the bone metastases of the BP naïve group compared to normal bone. No osteoclasts were detected in the BP-treated group. RANKL was predominantly expressed in osteoblasts and in the stromal elements of metastatic tissue. Conversely, RANK was present in osteoclasts of bone metastases and normal bone, as well as in tumor cells of metastatic lymph nodes and bone metastases. VEGF was strongly expressed in the control bone and bone metastases regardless of BP treatment. In summary, osteoclasts may not be the singular obligatory factor for osteolysis in bone metastases. An increased expression of RANKL in stromal tissue surrounding bone metastases, RANK in osteoclasts and VEGF may serve as future targeted therapies possibly in conjunction with bisphosphonates. The mechanisms for osteoclast expression and the expression of RANKL, RANK, OPG and VEGF merit further prospective analysis, particularly in the context of BP treatment and progressive bone metastases.
双膦酸盐（BPs）在降低骨转移患者骨相关事件（SREs）方面的益处主要归因于其强大的破骨细胞抑制作用。然而，尽管使用了包括强效双膦酸盐在内的现代全身抗癌疗法，许多骨转移患者仍会发生骨相关事件。对骨破坏基本机制的深入了解有助于进一步开发合适的靶向治疗方法。在本研究中，对转移性乳腺癌患者的存档石蜡包埋骨转移标本进行检查，以确定破骨细胞的存在、核因子κB受体激活剂（RANK）、RANK配体（RANKL）、骨保护素（OPG）和血管内皮生长因子（VEGF）的表达情况。有原发性乳腺癌、淋巴结转移、正常乳腺和正常骨组织的组织学标本可供比较。有20例未接受双膦酸盐治疗的患者和2例接受双膦酸盐治疗的患者的骨转移标本。与正常骨相比，未接受双膦酸盐治疗组的骨转移中破骨细胞显著增加。在接受双膦酸盐治疗组中未检测到破骨细胞。RANKL主要表达于成骨细胞和转移组织的基质成分中。相反，RANK存在于骨转移和正常骨的破骨细胞中，以及转移淋巴结和骨转移的肿瘤细胞中。无论是否接受双膦酸盐治疗，VEGF在对照骨和骨转移中均强烈表达。总之，破骨细胞可能不是骨转移中骨溶解的唯一必要因素。骨转移周围基质组织中RANKL表达增加、破骨细胞中RANK表达增加以及VEGF表达增加可能作为未来的靶向治疗方法，可能与双膦酸盐联合使用。破骨细胞表达以及RANKL、RANK、OPG和VEGF表达的机制值得进一步前瞻性分析，特别是在双膦酸盐治疗和进行性骨转移的背景下。
