Yoneda Toshiyuki, Tanaka Soichi, Hata Kenji
Toshiyuki Yoneda, Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
World J Orthop. 2013 Oct 18;4(4):178-85. doi: 10.5312/wjo.v4.i4.178.
Bone is one of the most preferential metastatic target sites of breast cancer. Bone possesses unique biological microenvironments in which various growth factors are stored and continuously released through osteoclastic bone resorption, providing fertile soil for circulating breast cancer cells. Bone-disseminated breast cancer cells in turn produce osteotropic cytokines which modulate bone environments. Under the influences of breast cancer-produced cytokines, osteoblasts express elevated levels of Ligand for receptor activator of nuclear factor-κB (RANKL) and stimulate osteoclastogenesis via binding to the receptor receptor activator of nuclear factor-κB (RANK) and activating its downstream signaling pathways in hematopoietic osteoclast precursors, which causes further osteoclastic bone destruction. Establishment of crosstalk with bone microenvironments (so called vicious cycle) is an essential event for metastatic breast cancer cells to develop bone metastasis. RANKL and RANK play a central role in this crosstalk. Moreover, recent studies have demonstrated that RANKL and RANK are involved in tumorigenesis and distant metastasis independent of bone microenvironments. Pharmacological disruption of the RANKL/RANK interplay should be an effective therapeutic intervention for primary breast tumors and bone and non-bone metastasis. In this context, denosumab, which is neutralizing monoclonal antibody against RANKL, is a mechanism-based drug for the treatment of bone metastases and would be beneficial for breast cancer patients with bone metastases and potentially visceral organ metastases.
骨是乳腺癌最优先转移的靶位点之一。骨拥有独特的生物微环境，各种生长因子储存于其中，并通过破骨细胞的骨吸收作用持续释放，为循环中的乳腺癌细胞提供了肥沃的土壤。播散至骨的乳腺癌细胞反过来产生促骨细胞因子，调节骨环境。在乳腺癌产生的细胞因子影响下，成骨细胞表达核因子κB受体活化因子配体（RANKL）水平升高，并通过与造血破骨细胞前体中的核因子κB受体活化因子（RANK）结合并激活其下游信号通路来刺激破骨细胞生成，这会导致进一步的破骨性骨破坏。与骨微环境建立相互作用（即所谓的恶性循环）是转移性乳腺癌细胞发生骨转移的关键事件。RANKL和RANK在这种相互作用中起核心作用。此外，最近的研究表明，RANKL和RANK独立于骨微环境参与肿瘤发生和远处转移。对RANKL/RANK相互作用进行药理学阻断应该是对原发性乳腺肿瘤以及骨和非骨转移的一种有效的治疗干预措施。在此背景下，地诺单抗是一种抗RANKL的中和单克隆抗体，是一种基于作用机制的治疗骨转移的药物，对伴有骨转移以及潜在内脏器官转移的乳腺癌患者有益。
