Soluble receptor activator of nuclear factor kappaB Fc diminishes prostate cancer progression in bone.
Soluble receptor activator of nuclear factor kappaB Fc diminishes prostate cancer progression in bone.
复制标题
DOI：
--
复制
发表时间：
2003-11
期刊：
影响因子：
11.2
通讯作者：
Jian Zhang;Jinlu Dai;Z. Yao;Yi Lu;W. Dougall;E. Keller
中科院分区：
文献类型：
--
作者：
Jian Zhang;Jinlu Dai;Z. Yao;Yi Lu;W. Dougall;E. Keller
前列腺癌(CAP)发展为骨转移病变，包括骨硬化和骨溶解的混合体。我们以前已经证明，靶向核因子kappaB受体激活剂配体(RANKL)和护骨素(OPG)可以阻止CAP的溶骨活性和它在骨中建立肿瘤的能力。然而，OPG可以阻断肿瘤坏死因子相关的凋亡诱导配体(TRAIL)介导的细胞凋亡，提示临床应用OPG可能阻止TRAIL介导的肿瘤细胞凋亡。因此，除OPG外，阻断RANKL活性的方法可能很重要。因此，我们评估了可溶性小鼠RANK-Fc(sRANK-Fc)在严重联合免疫缺陷小鼠中预防已建立的CAP进展的能力。我们首次证实sRANK在体外不能阻断TRAIL介导的LuCaP细胞的凋亡，但在体外确实能阻断LuCaP条件培养液诱导的破骨细胞生成。然后，将LuCaP35帽细胞注射到植入人胎骨的严重联合免疫缺陷小鼠的骨髓腔内，并允许其形成肿瘤6周。然后用赋形剂或sRANK-FC给药6周。放射照片、骨密度测量和骨组织形态计量学证明，sRANK-Fc可减少肿瘤引起的成骨细胞损伤。SRANK-Fc还可降低全身骨重建标记物，包括血清骨钙素、骨特异性碱性磷酸酶和尿胶原N-端肽。最后，sRANK-Fc降低了血清前列腺特异性抗原水平和骨中肿瘤体积，这表明肿瘤负担减少了。相反，sRANK-Fc对S.C.植入LuCaP细胞。结论：sRANK-Fc是一种有效的RANKL抑制剂，可通过抑制骨重建来抑制骨帽的生长。
Prostate cancer (CaP) develops metastatic bone lesions that consist of a mixture of osteosclerosis and osteolysis. We have previously demonstrated that targeting receptor activator of nuclear factor kappaB ligand (RANKL) with osteoprotegerin (OPG) prevents the osteolytic activity of CaP and its ability to establish tumor in bone. However, OPG can block tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, suggesting that the clinical use of OPG may prevent apoptosis of tumors mediated by TRAIL. Thus, methods to block RANKL activity, other than OPG, may be important. Accordingly, we evaluated the ability of soluble murine RANK-Fc (sRANK-Fc) to prevent progression of established CaP in a severe combined immunodeficient mouse implanted with fetal human bone. We first confirmed that sRANK did not block TRAIL-mediated apoptosis of LuCaP cells in vitro and that it did block LuCaP-conditioned media-induced osteoclastogenesis in vitro. Then, LuCaP 35 CaP cells were injected into the marrow space of the bone implanted in the severe combined immunodeficient mice implanted with fetal human bone and allowed to develop into tumors for 6 weeks. Either vehicle or sRANK-Fc was then administered for 6 weeks. sRANK-Fc diminished tumor-induced osteoblastic lesions as demonstrated by radiograph, bone mineral density measurement, and bone histomorphometry. sRANK-Fc also reduced systemic bone remodeling markers, including serum osteocalcin and bone-specific alkaline phosphatase and urine N-telopeptide of collagen. Finally, sRANK-Fc decreased serum prostate-specific antigen levels and tumor volume in the bone, which indicates decreased tumor burden. In contrast, sRANK-Fc had no effect on s.c. implanted LuCaP cells. We conclude that sRANK-Fc is an effective inhibitor of RANKL that diminishes progression of CaP growth in bone through inhibition of bone remodeling.