Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone
Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone
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DOI：
10.1016/j.bone.2008.09.009
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发表时间：
2009-01-01
期刊：
影响因子：
4.1
通讯作者：
Lieberman, Jay R.
中科院分区：
文献类型：
--
作者：
Virk, Mandeep S.;Petrigliano, Frank A.;Lieberman, Jay R.
骨转移是晚期前列腺癌患者发病和死亡的主要原因。考虑到肿瘤细胞和骨微环境之间复杂的相互作用，人们越来越关注开发针对肿瘤生长和骨微环境的联合疗法。在本研究中，我们研究了同时阻断 BMP 通路和 RANK/RANKL 轴对骨中溶骨性前列腺癌病变的影响。我们使用编码noggin（RetroNoggin）的逆转录病毒载体来拮抗BMPs和RANK：Fc的作用，RANK：Fc是一种重组RANKL拮抗剂，用于抑制RANK/RANKL轴。使用平片、后肢肿瘤测量、显微 PET/CT（(18)FDG 和 F-18-氟化物示踪剂）和组织学评估肿瘤生长和骨质流失。植入 PC-3 细胞的胫骨在两周内出现纯粹的溶骨性病变，并且在连续时间点皮质骨破坏逐渐增加。与未经治疗的对照动物中植入的胫骨相比，植入过表达头蛋白（RetroNoggin）的 PC-3 细胞的胫骨导致肿瘤尺寸减小并减少骨丢失。 RANK：在植入 PC-3 细胞的胫骨中，Fc 给药可抑制破骨细胞的形成，延缓溶骨性病变的发展，减少骨质流失并缩小肿瘤大小。与单独使用 noggin 过度表达治疗的植入胫骨相比，RANK:Fc 和 noggin 过度表达的联合治疗有效地延迟了溶骨性病变的放射学发展，并减少了骨丢失和肿瘤负荷。此外，与单独使用 RANK:Fc 治疗的动物相比，使用联合策略治疗的动物表现出骨质流失减少 (micro CT) 和肿瘤负荷降低 (FDG micro PET)。在骨中的溶骨性前列腺癌病变中，与单独抑制任一单独途径相比，联合阻断 RANK/RANKL 轴和 BMP 途径可减少肿瘤负荷并减少骨丢失。这些结果表明，同时靶向肿瘤细胞和破骨细胞可能是抑制体内已形成的溶骨转移性病变进展的最有效方法。 (C) 2008 Elsevier Inc. 保留所有权利。
Metastasis to bone is the leading cause of morbidity and mortality in advanced prostate cancer patients. Considering the complex reciprocal interactions between the tumor cells and the bone microenvironment, there is increasing interest in developing combination therapies targeting both the tumor growth and the bone microenvironment. In this Study, we investigated the effect of simultaneous blockade of BMP pathway and RANK/RANKL axis in an osteolytic prostate cancer lesion in bone. We used a retroviral vector encoding noggin (RetroNoggin) to antagonize the effect of BMPs and RANK:Fc, which is a recombinant RANKL antagonist was used to inhibit RANK/RANKL axis. The tumor growth and bone loss were evaluated using plain radiographs, hind limb tumor measurements, micro PET/CT ((18)FDG and F-18-fluoride tracer), and histology. Tibias implanted with PC-3 cells developed pure osteolytic lesions at 2-weeks with progressive increase in cortical bone destruction at successive time points. Tibias implanted with PC-3 cells over expressing noggin (RetroNoggin) resulted in reduced tumor size and decreased bone loss compared to the implanted tibias in untreated control animals. RANK: Fc administration inhibited the formation of osteoclasts, delayed the development of osteolytic lesions, decreased bone loss and reduced tumor size in tibias implanted with PC-3 cells. The combination therapy with RANK:Fc and noggin over expression effectively delayed the radiographic development of osteolytic lesions, and decreased the bone loss and tumor burden compared to implanted tibias treated with noggin over expression alone. Furthermore, the animals treated with the combination strategy exhibited decreased bone loss (micro CT) and lower tumor burden (FDG micro PET) compared to animals treated with RANK:Fc alone. Combined blockade of RANK/RANKL axis and BMP pathway resulted in reduced tumor burden and decreased bone loss compared to inhibition of either individual pathway alone in osteolytic prostate cancer lesion in bone. These results suggest that simultaneous targeting of tumor cells and osteoclasts may be the most effective method of inhibiting the progression of established osteolytic metastatic lesions in vivo. (C) 2008 Elsevier Inc. All rights reserved.