RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor, metastasis genes
RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor, metastasis genes
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DOI：
10.1002/pros.20678
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发表时间：
2008-01-01
期刊：
影响因子：
2.8
通讯作者：
Dougall, William C.
中科院分区：
文献类型：
--
作者：
Armstrong, Allison P.;Miller, Robert E.;Dougall, William C.
背景资料。骨转移是人类前列腺癌的常见并发症，会导致成骨细胞病变的发展，其中包括潜在的破骨细胞成分。以往在乳腺癌和前列腺癌啮齿动物模型中的研究已经证实，抑制核因子-kappa B受体激活剂(RANKL)可以减少骨病变的发展和骨中肿瘤的生长。RANK通过在破骨细胞及其前体细胞上的表达，对破骨细胞的分化、激活和存活起着至关重要的作用。RANK在某些肿瘤细胞类型如乳腺和结肠中也有表达，提示RANKL可能对肿瘤细胞起直接作用。方法：雄性CB17严重联合免疫缺陷(SCID)小鼠体内注射PC3细胞，并用PBS或RANKL拮抗剂人骨保护素(OPG)-FC治疗。X线片分析溶骨性病变的形成，并分析局部和全身RANKL和OPG水平。结果：OPG-FC治疗PC3肿瘤小鼠可减少病变形成和肿瘤负担。PC3荷瘤小鼠全身和局部RANKL表达水平升高。PC3细胞对RANKL的反应是通过激活多条信号通路，导致骨溶解和迁移相关基因的表达发生显着变化。RANKL的RANK激活导致PC3细胞通过胶原基质侵袭增加。结论：这些数据表明，由于PC3前列腺癌在骨骼内的生长，宿主间质RANKL是系统和局部诱导的。RANK在前列腺癌细胞上表达，并以RANKL依赖的方式促进侵袭。
BACKGROUND. 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-kappa B 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.METHODS. 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.RESULTS. 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.CONCLUSION. 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.