Canon Jude R, Roudier Martine, Bryant Rebecca, Morony Sean, Stolina Marina, Kostenuik Paul J, Dougall William C
Department of Oncology Research, Amgen Inc., Thousand Oaks, CA, USA.
Clin Exp Metastasis. 2008;25(2):119-29. doi: 10.1007/s10585-007-9127-1. Epub 2007 Dec 5.
Bone metastases cause severe skeletal morbidity including fractures and hypercalcemia. Tumor cells in bone induce activation of osteoclasts, which mediate bone resorption and release of growth factors from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. Receptor activator of NF-kappaB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival, and is blocked by a soluble decoy receptor, osteoprotegerin (OPG). In human malignancies that metastasize to bone, dysregulation of the RANK/RANKL/OPG pathway can increase the RANKL:OPG ratio, a condition which favors excessive osteolysis. In a mouse model of bone metastasis, RANKL protein levels in MDA-MB-231 (MDA-231) tumor-bearing bones were significantly higher than tumor-free bones. The resulting tumor-induced osteoclastogenesis and osteolysis was dose-dependently inhibited by recombinant OPG-Fc treatment, supporting the essential role for RANKL in this process. Using bioluminescence imaging in a mouse model of metastasis, we monitored the anti-tumor efficacy of RANKL inhibition on MDA-231 human breast cancer cells in a temporal manner. Treatment with OPG-Fc in vivo inhibited growth of MDA-231 tumor cells in bony sites when given both as a preventative (dosed day 0) and as a therapeutic agent for established bone metastases (dosed day 7). One mechanism by which RANKL inhibition reduced tumor burden appears to be indirect through inhibition of the "vicious cycle" and involved an increase in tumor cell apoptosis, as measured by active caspase-3. Here, we demonstrate for the first time that OPG-Fc treatment of mice with established bone metastases resulted in an overall improvement in survival.
骨转移会导致严重的骨骼病变，包括骨折和高钙血症。骨中的肿瘤细胞会诱导破骨细胞活化，破骨细胞介导骨吸收并从骨基质中释放生长因子，从而导致骨破坏和肿瘤增殖的“恶性循环”。核因子κB受体活化因子配体（RANKL）是破骨细胞形成、功能和存活的关键介质，并被可溶性诱饵受体骨保护素（OPG）所阻断。在发生骨转移的人类恶性肿瘤中，RANK/RANKL/OPG通路失调会增加RANKL:OPG比值，这种情况有利于过度骨溶解。在骨转移小鼠模型中，携带MDA-MB-231（MDA-231）肿瘤的骨骼中RANKL蛋白水平显著高于无肿瘤的骨骼。重组OPG-Fc处理可剂量依赖性地抑制由此产生的肿瘤诱导的破骨细胞生成和骨溶解，支持RANKL在这一过程中的关键作用。利用转移小鼠模型中的生物发光成像，我们以时间序列监测了RANKL抑制对MDA-231人乳腺癌细胞的抗肿瘤疗效。当作为预防剂（第0天给药）和已发生骨转移的治疗剂（第7天给药）时，体内给予OPG-Fc均可抑制MDA-231肿瘤细胞在骨部位的生长。RANKL抑制减轻肿瘤负担的一种机制似乎是通过抑制“恶性循环”间接实现的，并且涉及肿瘤细胞凋亡增加，这通过活性半胱天冬酶-3来衡量。在此，我们首次证明，用OPG-Fc治疗已发生骨转移的小鼠可使总体生存率得到改善。
