Virk Mandeep S, Petrigliano Frank A, Liu Nancy Q, Chatziioannou Arion F, Stout David, Kang Christine O, Dougall William C, Lieberman Jay R
Department of Orthopaedic Surgery, The New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, CT 06030-5456, USA.
Bone. 2009 Jan;44(1):160-7. doi: 10.1016/j.bone.2008.09.009. Epub 2008 Sep 26.
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 (18)F-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.
骨转移是晚期前列腺癌患者发病和死亡的主要原因。考虑到肿瘤细胞与骨微环境之间复杂的相互作用，开发针对肿瘤生长和骨微环境的联合疗法越来越受到关注。在本研究中，我们研究了同时阻断骨形态发生蛋白（BMP）信号通路和RANK/RANKL轴对骨溶骨性前列腺癌病变的影响。我们使用编码头蛋白（RetroNoggin）的逆转录病毒载体来拮抗BMP的作用，并使用RANK:Fc（一种重组RANKL拮抗剂）来抑制RANK/RANKL轴。通过X线平片、后肢肿瘤测量、微型PET/CT（（18）FDG和（18）F-氟化物示踪剂）以及组织学评估肿瘤生长和骨质流失情况。植入PC-3细胞的胫骨在2周时出现单纯溶骨性病变，随后各时间点皮质骨破坏逐渐加重。与未治疗的对照动物植入胫骨相比，植入过表达头蛋白（RetroNoggin）的PC-3细胞的胫骨肿瘤大小减小，骨质流失减少。给予RANK:Fc可抑制破骨细胞形成，延缓溶骨性病变发展，减少植入PC-3细胞的胫骨骨质流失并减小肿瘤大小。与单独过表达头蛋白处理的植入胫骨相比，RANK:Fc与头蛋白过表达的联合治疗有效延缓了溶骨性病变的影像学发展，并减少了骨质流失和肿瘤负荷。此外，与单独使用RANK:Fc治疗的动物相比，采用联合策略治疗的动物骨质流失减少（微型CT），肿瘤负荷降低（FDG微型PET）。与单独抑制骨溶骨性前列腺癌病变中的任何一条单独途径相比，联合阻断RANK/RANKL轴和BMP信号通路可降低肿瘤负荷并减少骨质流失。这些结果表明，同时靶向肿瘤细胞和破骨细胞可能是体内抑制已建立的溶骨性转移病变进展的最有效方法。
