Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals
Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals
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DOI：
10.1002/ijc.23903
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发表时间：
2009-01-01
影响因子：
6.4
通讯作者：
Nakamura, Hiroaki
中科院分区：
文献类型：
--
作者：
Hiraga, Toru;Nakamura, Hiroaki
甲磺酸伊马替尼（伊马替尼）是一种有效的和选择性的酪氨酸激酶，Bcr-Abl，c-Kit和血小板衍生生长因子受体（PDGFR）的抑制剂。最近，据报道，伊马替尼也靶向巨噬细胞集落刺激因子（M-CSF）受体c-Fms。M-CSF信号对于破骨细胞的分化是必不可少的。乳腺癌的骨转移常伴有骨质破坏。此外，一些证据表明，破骨细胞在骨转移的发展和进展中起着核心作用。因此，在本研究中，我们研究了伊马替尼对乳腺癌骨转移的影响。免疫共沉淀试验表明，伊马替尼抑制M-CSF诱导的破骨细胞前体细胞中c-Fms的磷酸化以及PDGF诱导的MDA-MB-231人乳腺癌细胞中PDGFR的磷酸化。伊马替尼也显着减少破骨细胞的形成在体外。相反，这些浓度的伊马替尼并不影响成骨细胞的分化。然后，我们在裸鼠模型中检测了伊马替尼对MDA-MB-231细胞骨转移的影响。放射学和组织形态学分析表明，伊马替尼显着减少骨转移与破骨细胞数量减少。为了支持c-Fms的抑制作用抑制骨转移的发展的观点，我们发现c-Fms的特异性抑制剂Ki 20227也减少了骨转移。总之，这些结果共同表明，伊马替尼减少骨转移，至少部分，通过抑制骨细胞的骨破坏通过阻断c-Fms信号。我们的研究结果还表明，伊马替尼可能对癌症治疗引起的骨丢失有保护作用。(C)2008 Wiley-Liss，Inc.
Imatinib mesylate (imatinib) is a potent and selective inhibitor of the tyrosine kinases, Bcr-Abl, c-Kit and platelet-derived growth factor receptors (PDGFRs). Recently, it has been reported that imatinib also targets the macrophage colony-stimulating factor (M-CSF) receptor c-Fms. M-CSF signals are essential for the differentiation of osteoclasts. Bone metastases of breast cancer are frequently associated with osteoclastic bone destruction. Furthermore, several lines of evidence suggest that osteoclasts play central roles in the development and progression of bone metastases. Thus, in the present study, we examined the effects of imatinib on bone metastases of breast cancer. Coimmunoprecipitation assays showed that imatinib inhibited the M-CSF-induced phosphorylation of c-Fms in osteoclast precursor cells as well as the PDGF-induced PDGFR phosphorylation in MDA-MB-231 human breast cancer cells. Imatinib also markedly reduced osteoclast formation in vitro. In contrast, those concentrations of imatinib did not affect osteoblast differentiation. We then examined the effects of imatinib on bone metastases of MDA-MB-231 cells in a nude mouse model. Radiographic and histomorphometric analyses demonstrated that imatinib significantly decreased bone metastases associated with the reduced number of osteoclasts. In support of the notion that the inhibition of c-Fms acts to suppress the development of bone metastases, we found that a specific inhibitor of c-Fms Ki20227 also decreased bone metastases. In conclusion, these results collectively suggest that imatinib reduced bone metastases, at least in part, by inhibiting osteoclastic bone destruction through the blockade of c-Fms signals. Our results also suggest that imatinib may have a protective effect against cancer treatment-induced bone loss. (C) 2008 Wiley-Liss, Inc.