Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases.
Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases.
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DOI：
10.1158/0008-5472.can-11-3061
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发表时间：
2012-08-15
期刊：
影响因子：
11.2
通讯作者：
Yoneda T
中科院分区：
文献类型：
--
作者：
Hiraga T;Myoui A;Hashimoto N;Sasaki A;Hata K;Morita Y;Yoshikawa H;Rosen CJ;Mundy GR;Yoneda T
骨吸收后骨储存生长因子的持续释放促进循环癌细胞的定植。然而，各种生长因子中的每一种的确切作用仍不清楚。在这项研究中，我们研究了骨源性胰岛素样生长因子（IGF）在乳腺癌动物模型骨转移发展中的作用。我们发现，在细胞接种之前局部刺激颅骨骨吸收刺激随后的骨转移到该部位在体内，而抑制骨吸收抑制骨转移。锚定非依赖性生长的癌细胞被刺激的培养上清液从吸收骨，其中含有升高水平的IGF-1型（IGF-1）。这种刺激被IGF-1受体（IGF 1 R）中和抗体阻断，但不被靶向其他骨储存生长因子（包括TGFβ、成纤维细胞生长因子和血小板衍生生长因子）的抗体阻断。虽然重组人IGF-I引起IGFIR酪氨酸自磷酸化，随后激活癌细胞中的Akt和NF-κB，但IGFIR、Akt或NF-κB的显性负性抑制显著减少骨转移，并增加转移细胞中的凋亡和减少有丝分裂。总之，我们的研究结果表明，骨源性IGF-I通过激活IGFIR/Akt/NF-κB通路来桥接骨和转移癌细胞之间的串扰。因此，该途径的破坏可能代表骨转移的有希望的治疗干预。
The continuous release of bone-stored growth factors following bone resorption promotes the colonization of circulating cancer cells. However, the precise role of each of the various growth factors remains unclear. In this study, we investigated the role of bone-derived insulin-like growth factor (IGF) in the development of bone metastases in an animal model of breast cancer. We found that local stimulation of calvarial bone resorption prior to cell inoculation stimulated subsequent bone metastases to that site in vivo, while inhibition of bone resorption inhibited bone metastases. Anchorage-independent growth of cancer cells was stimulated by the culture supernatants from resorbed bones, which contained elevated levels of IGF type I (IGF-1). This stimulation was blocked by IGF-1 receptor (IGF1R) neutralizing antibody, but not antibody targeting other bone-stored growth factors including TGFβ, fibroblast growth factors, and platelet derived growth factors. While recombinant human IGF-I caused IGFIR tyrosine autophosphorylation, followed by activation of Akt and NF-κB in cancer cells, dominant-negative inhibition of IGFIR, Akt, or NF-κB significantly reduced bone metastases with increased apoptosis and decreased mitosis in metastatic cells. Together, our findings suggest that bone-derived IGF-I bridges the crosstalk between bone and metastasized cancer cells via activation of the IGFIR/Akt/NF-κB pathway. Disruption of this pathway therefore may represent a promising therapeutic intervention for bone metastasis.