Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically
Osteoprotegerin overexpression by breast cancer cells enhances orthotopic and osseous tumor growth and contrasts with that delivered therapeutically
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DOI：
10.1158/0008-5472.can-05-3119
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Gillespie, MT
中科院分区：
文献类型：
--
作者：
Fisher, JL;Thomas-Mudge, RJ;Gillespie, MT
护骨素(OPG)是核因子-kappaB受体激活剂(RANKL)的诱饵受体，RANKL是破骨细胞形成的关键分子。在体外，OPG抑制破骨细胞的形成，在体内(作为FC-OPG给药)，它可以减少高钙血症和建立小鼠骨肿瘤细胞生长模型的溶骨性病变。乳腺癌细胞产生的甲状旁腺激素相关蛋白(PTHrP)可导致成骨细胞RANKL/OPG比值增加，从而诱导骨溶解。我们检测了局部产生OPG对乳腺癌细胞在骨和乳脂垫中建立和生长能力的影响。将全长OPG导入MCF-7细胞或高表达PTHrP的MCF-7细胞，接种于裸鼠胫骨近端。注射过表达PTHrP和OPG的细胞的小鼠肿瘤生长加快，骨溶解增加(与过表达PTHrP的MCF-7细胞相比增加了2倍)，组织学改变，反映出与MCF-7细胞相比，分化较低(更具侵袭性)的表型。相反，即使在接种了OPG过表达细胞的小鼠中，给予重组FC-OPG也减少了肿瘤的生长和限制了骨溶解。类似地，乳腺癌细胞过表达OPG促进了原位接种后的肿瘤生长。这些结果表明，乳腺癌细胞过表达OPG促进了体内肿瘤的生长，治疗用FC-OPG和肿瘤细胞产生的全长OPG的反应有显著不同。
Osteoprotegerin (OPG) acts as a decoy receptor for receptor activator of NF-kappa B ligand (RANKL), which is a pivotal molecule required for osteoclast formation. In vitro OPG inhibits osteoclast formation and in vivo (administered as Fc-OPG) it reduces hypercalcemia and the establishment of osteolytic lesions in mouse models of tumor cell growth in bone. Osteolysis can be induced by parathyroid hormone-related protein (PTHrP) produced by breast cancer cells that results in an increased osteoblastic RANKL/OPG ratio. We examined the effect of local tumor production of OPG on the ability of breast cancer cells to establish and grow in bone and mammary fat pad. MCF-7 cells or MCF-7 cells overexpressing PTHrP were transfected with full-length OPG and inoculated into the proximal tibiae of athymic nude mice. Mice injected with cells overexpressing PTHrP and OPG showed enhanced tumor growth, increased osteolysis (2-fold compared with MCF-7 cells overexpressing PTHrP), and altered histology that was reflective of a less differentiated (more aggressive) phenotype compared with MCF-7 cells. In contrast, administration of recombinant Fc-OPG reduced tumor growth and limited osteolysis even in mice inoculated with OPG overexpressing cells. Similarly, OPG overexpression by breast cancer cells enhanced tumor growth following orthotopic inoculation. These results indicate that OPG overexpression by breast cancer cells increases tumor growth in vivo and that there are strikingly different responses between therapeutically administered Fc-OPG and full-length OPG produced by tumor cells.