Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion.
Combined inhibition of the BMP pathway and the RANK-RANKL axis in a mixed lytic/blastic prostate cancer lesion.
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DOI：
10.1016/j.bone.2010.11.003
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发表时间：
2011-03-01
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.;Alaee, Farhang;Petrigliano, Frank A.;Sugiyama, Osamu;Chatziioannou, Arion F.;Stout, David;Dougall, William C.;Lieberman, Jay R.
关键词：
本研究的目的是探讨联合抑制核因子kappaB受体激活剂(RANKL)和骨形态发生蛋白(BMP)活性对前列腺癌骨内溶解/母细胞混合性病变的影响。将人前列腺癌细胞(C42b)注射到免疫低下的小鼠体内，采用胫骨内注射模型，制造混合的裂解/母细胞病变。每周三次皮下注射重组RANKL拮抗剂RANKL-Fc(10 mg/kg)，以抑制RANKL及随后的破骨细胞的形成、功能和存活。BMP活性的抑制是通过用表达noggin的逆转录病毒载体(retronoggin；RN)体外转导前列腺癌细胞来实现的。共设3个治疗组(RANK-FC治疗、RN治疗及RN与RANK-FC联合治疗)和2个对照组(RN治疗组未治疗对照和空载体对照)。通过X线平片、后肢肿瘤大小、18F-脱氧葡萄糖和18F-氟化物微型PET-CT、组织学和组织形态计量学评价骨病变进展和肿瘤生长情况。单独使用RANK-FC治疗可抑制骨溶解，并将溶骨性/母细胞性混合病变转变为成骨表型。RN单独治疗抑制了溶骨性/母细胞性混合病变中的成骨成分，并导致形成较小的溶骨性骨病变和较小的软组织尺寸。RN和RANK-FC均能延缓骨损伤的发展，抑制骨溶解，抑制小的软组织肿瘤，保留骨结构，肿瘤诱导的新骨形成较少。本研究提示，联合抑制RANKL和BMP通路可能是一种有效的生物治疗方法，可以抑制已建立的溶血性/母细胞性前列腺癌骨内病变的进展。
The purpose of this study was to investigate the influence of combined inhibition of RANKL (receptor activator of nuclear factor kappa-B ligand) and bone morphogenetic protein (BMP) activity in a mixed lytic/blastic prostate cancer lesion in bone. Human prostate cancer cells (C4 2b) were injected into immunocompromised mice using an intratibial injection model to create mixed lytic/blastic lesions. RANK-Fc, a recombinant RANKL antagonist, was injected subcutaneously three times a week (10mg/kg) to inhibit RANKL and subsequent formation, function and survival of osteoclasts. Inhibition of BMP activity was achieved by transducing prostate cancer cells ex vivo with a retroviral vector expressing noggin (retronoggin; RN). There were three treatment groups (RANK-Fc treatment, RN treatment and combined RN and RANK-Fc treatment) and two control groups (untreated control and empty vector control for the RN treatment group). The progression of bone lesion and tumor growth was evaluated using plain radiographs, hind limb tumor size, 18F-Fluorodeoxyglucose and 18F-fluoride micro PET-CT, histology and histomorphometry. Treatment with RANK-Fc alone inhibited osteolysis and transformed a mixed lytic/blastic lesion into an osteoblastic phenotype. Treatment with RN alone inhibited the osteoblastic component in a mixed lytic/blastic lesion and resulted in formation of smaller osteolytic bone lesion with smaller soft tissue size. The animals treated with both RN and RANK-Fc demonstrated delayed development of bone lesions, inhibition of osteolysis, small soft tissue tumors and preservation of bone architecture with less tumor induced new bone formation. This study suggests that combined inhibition of the RANKL and the BMP pathway may be an effective biologic therapy to inhibit the progression of established mixed lytic/blastic prostate cancer lesions in bone.
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