Armstrong Allison P, Miller Robert E, Jones Jon C, Zhang Jian, Keller Evan T, Dougall William C
Department of Hematology, Amgen Inc., Seattle, Washington 98119, USA.
Prostate. 2008 Jan 1;68(1):92-104. doi: 10.1002/pros.20678.
Metastases to bone are a frequent complication of human prostate cancer and result in the development of osteoblastic lesions that include an underlying osteoclastic component. Previous studies in rodent models of breast and prostate cancer have established that receptor activator of NF-kappaB ligand (RANKL) inhibition decreases bone lesion development and tumor growth in bone. RANK is essential for osteoclast differentiation, activation, and survival via its expression on osteoclasts and their precursors. RANK expression has also been observed in some tumor cell types such as breast and colon, suggesting that RANKL may play a direct role on tumor cells.
Male CB17 severe combined immunodeficient (SCID) mice were injected with PC3 cells intratibially and treated with either PBS or human osteprotegerin (OPG)-Fc, a RANKL antagonist. The formation of osteolytic lesions was analyzed by X-ray, and local and systemic levels of RANKL and OPG were analyzed. RANK mRNA and protein expression were assessed on multiple prostate cancer cell lines, and events downstream of RANK activation were studied in PC3 cells in vitro.
OPG-Fc treatment of PC3 tumor-bearing mice decreased lesion formation and tumor burden. Systemic and local levels of RANKL expression were increased in PC3 tumor bearing mice. PC3 cells responded to RANKL by activating multiple signaling pathways which resulted in significant changes in expression of genes involved in osteolysis and migration. RANK activation via RANKL resulted in increased invasion of PC3 cells through a collagen matrix.
These data demonstrate that host stromal RANKL is induced systemically and locally as a result of PC3 prostate tumor growth within the skeleton. RANK is expressed on prostate cancer cells and promotes invasion in a RANKL-dependent manner.
骨转移是人类前列腺癌常见的并发症，会导致成骨细胞病变的发生，其中包括潜在的破骨细胞成分。先前在乳腺癌和前列腺癌啮齿动物模型中的研究表明，核因子κB受体活化因子配体（RANKL）抑制可减少骨病变的发展以及骨内肿瘤的生长。RANK通过在破骨细胞及其前体上表达，对破骨细胞的分化、活化和存活至关重要。在一些肿瘤细胞类型如乳腺癌和结肠癌中也观察到了RANK表达，这表明RANKL可能在肿瘤细胞上发挥直接作用。
将PC3细胞经胫骨内注射到雄性CB17严重联合免疫缺陷（SCID）小鼠体内，并用磷酸盐缓冲液（PBS）或人骨保护素（OPG）-Fc（一种RANKL拮抗剂）进行治疗。通过X射线分析溶骨性病变的形成，并分析RANKL和OPG的局部和全身水平。在多个前列腺癌细胞系上评估RANK mRNA和蛋白表达，并在体外对PC3细胞中RANK活化的下游事件进行研究。
用OPG-Fc治疗携带PC3肿瘤的小鼠可减少病变形成和肿瘤负荷。携带PC3肿瘤的小鼠体内RANKL表达的全身和局部水平均升高。PC3细胞通过激活多种信号通路对RANKL作出反应，这导致参与骨溶解和迁移的基因表达发生显著变化。通过RANKL激活RANK导致PC3细胞通过胶原基质的侵袭增加。
这些数据表明，由于PC3前列腺肿瘤在骨骼内生长，宿主基质RANKL在全身和局部被诱导。RANK在前列腺癌细胞上表达，并以RANKL依赖的方式促进侵袭。
