Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma.
Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma.
复制标题
APO2L/TRAIL在多发性骨髓瘤的鼠模型中抑制肿瘤的生长和骨骼破坏。
DOI：
10.1158/1078-0432.ccr-08-2444
复制
发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Evdokiou A
中科院分区：
文献类型：
--
作者：
Labrinidis A;Diamond P;Martin S;Hay S;Liapis V;Zinonos I;Sims NA;Atkins GJ;Vincent C;Ponomarev V;Findlay DM;Zannettino AC;Evdokiou A
多发性骨髓瘤是一种无法治愈的疾病，需要开发新的治疗方法。在这里，我们报告了重组可溶性Apo 2L/肿瘤坏死因子相关凋亡诱导配体（TRAIL）在异种人多发性骨髓瘤模型中抑制肿瘤进展和骨破坏的疗效。我们建立了一种小鼠骨髓瘤模型，其中Apo 2L/TRAIL敏感的RPMI-8226或KMS-11细胞，用三重报告基因构建体（NES-HSV-TK/GFP/Luc）标记，直接移植到裸鼠的胫骨骨髓腔中。通过生物发光成像逐步监测肿瘤负荷，并使用高分辨率体内显微计算机断层扫描测量骨髓瘤诱导的骨质溶解的发展。在移植Apo 2L/TRAIL敏感的RPMI-8226或KMS-11细胞的小鼠的胫骨骨髓腔中，肿瘤负荷进行性增加，与癌细胞移植区域中直接的广泛骨质溶解相关。用重组可溶性Apo 2L/TRAIL治疗小鼠可降低骨髓腔中的骨髓瘤负荷，并显著保护小鼠免受骨髓瘤诱导的骨质溶解。Apo 2L/TRAIL治疗对骨的保护作用是通过Apo 2L/TRAIL对骨微环境中骨髓瘤细胞的直接凋亡作用介导的。这是第一项研究重组Apo 2L/TRAIL对骨微环境中骨髓瘤负荷和相关骨髓瘤诱导的骨破坏的疗效的体内研究。我们的研究结果表明，重组可溶性Apo 2L/TRAIL减少骨髓瘤的负担在骨微环境中，并保护骨免受骨髓瘤诱导的骨破坏反对骨保护素在Apo 2L/TRAIL诱导的细胞凋亡在体内的抑制作用，并强调需要临床评估Apo 2L/TRAIL在多发性骨髓瘤患者。
Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma. We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography. Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment. This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma.