RANK ligand is a prerequisite for cancer-associated osteolytic lesions
RANK ligand is a prerequisite for cancer-associated osteolytic lesions
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DOI：
10.1002/path.1199
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发表时间：
2002-10-01
影响因子：
7.3
通讯作者：
Kitazawa, R
中科院分区：
文献类型：
--
作者：
Kitazawa, S;Kitazawa, R
乳腺癌常伴有溶骨性骨转移，其中破骨细胞在骨破坏中起主要作用。最近，破骨细胞分化因子（RANKL）已被确定为从造血前体细胞的破骨细胞的形成和维持的先决条件。为了阐明破骨细胞生成和骨破坏在骨驻留的乳腺癌的机制，产生PTHrP（MCF-7）和非生产（MCF-7 UP）的人乳腺癌细胞皮下注射到裸小鼠的前额保持没有雌激素补充。术后1周、2周、3周，采用原位杂交和TRAP染色检测RANKL和PTHrP mRNA的表达及破骨细胞的生成。在MCF-7细胞中，早期骨表面的梭形基质细胞和成骨细胞表达RANKL，然后在骨膜骨表面诱导大量破骨细胞。移植后三周，MCF-7癌细胞迁移到侵蚀的骨表面，在那里它们存活下来。在所有阶段，RANKL表达仅限于基质/成骨细胞，而PTHrP仅限于MCF-7乳腺癌细胞。另一方面，PTHrP在MCF-7 UP细胞中在所有阶段均为阴性，既未观察到破骨细胞的诱导，也未观察到癌细胞的浸润性生长。此外，PTHrP体外处理导致MC 3 T3-E1小鼠成骨细胞系中RANKL mRNA表达和转录活性增加。因此，PTHrP通过基质/成骨细胞上RANKL基因的反式激活诱导骨细胞骨吸收，提供有利于产生PTHrP的癌细胞存活的骨微环境。版权所有（C）2002约翰威利父子有限公司
Breast cancer is frequently associated with osteolytic bone metastasis, where osteoclasts play a major role in bone destruction. Recently, osteoclast differentiation factor (RANKL) has been identified as a prerequisite for the formation and maintenance of osteoclasts from haematopoietic precursors. To elucidate the mechanism of osteoclastogenesis and bone destruction in bone-residing breast cancer, PTHrP-producing (MCF-7) and -non-producing (MCF-7UP) human breast cancer cells were subcutaneously injected into the forehead of nude mice maintained without oestrogen supplement. One, two, and three weeks thereafter, the expression of RANKL and PTHrP mRNA, and osteoclastogenesis were analysed by in situ hybridization and TRAP staining. In MCF-7 cells, at early stages, spindle-shaped stromal cells and osteoblasts on the bone surface expressed RANKL, then numerous osteoclasts were induced on the periosteal bone surface. Three weeks after the transplantation, MCF-7 cancer cells migrated onto the eroded bone surface, where they survived apoptosis. At all stages, RANKL expression was confined to the stromal/osteoblastic cells, whereas PTHrP was confined to the MCF-7 breast cancer cells. On the other hand, PTHrP was negative in MCF-7UP cells at all stages, and neither induction of osteoclasts nor infiltrative growth of cancer cells was observed. Moreover, in vitro treatment with PTHrP resulted in increased RANKL mRNA expression and transcription activity in the MC3T3-E1 mouse osteoblastic cell line. Thus PTHrP induces osteoclastic bone resorption through the transactivation of the RANKL gene on stromal/osteoblastic cells, affording a bone microenvironment conducive to the survival of PTHrP-producing cancer cells. Copyright (C) 2002 John Wiley Sons, Ltd.