Breast cancer cell-derived fibroblast growth factors enhance osteoclast activity and contribute to the formation of metastatic lesions.
Breast cancer cell-derived fibroblast growth factors enhance osteoclast activity and contribute to the formation of metastatic lesions.
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DOI：
10.1371/journal.pone.0185736
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Schwertfeger KL
中科院分区：
文献类型：
--
作者：
Aukes K;Forsman C;Brady NJ;Astleford K;Blixt N;Sachdev D;Jensen ED;Mansky KC;Schwertfeger KL
成纤维细胞生长因子（FGF）及其受体（FGFR）参与促进乳腺癌的生长和进展。虽然已经广泛研究了肿瘤细胞中FGFR活化的自分泌作用，但关于肿瘤细胞来源的FGF对微环境中细胞的作用知之甚少。由于FGF信号转导与骨形成和破骨细胞分化的调节有关，我们假设肿瘤细胞来源的FGF能够调节破骨细胞功能并促进骨转移病灶的生长。在破骨细胞分化过程中检测FGFR表达的初步研究显示，在分化过程中破骨细胞中FGFR 1的表达增加。因此，进行研究以确定肿瘤细胞来源的FGF是否能够促进破骨细胞分化和活性。使用非转化和转化的细胞系，我们证明乳腺癌细胞表达许多已知激活FGFR1的FGF配体。此外，我们的结果表明，使用临床相关抑制剂BGJ398抑制FGFR活性导致体外破骨细胞分化和活性降低。用BGJ398治疗将肿瘤细胞注射到股骨中的小鼠导致破骨细胞活性降低和骨破坏。总之，这些研究表明，肿瘤细胞衍生的FGF增强破骨细胞功能，并有助于乳腺癌转移性病变的形成。
Fibroblast growth factors (FGFs) and their receptors (FGFRs) have been implicated in promoting breast cancer growth and progression. While the autocrine effects of FGFR activation in tumor cells have been extensively studied, little is known about the effects of tumor cell-derived FGFs on cells in the microenvironment. Because FGF signaling has been implicated in the regulation of bone formation and osteoclast differentiation, we hypothesized that tumor cell-derived FGFs are capable of modulating osteoclast function and contributing to growth of metastatic lesions in the bone. Initial studies examining FGFR expression during osteoclast differentiation revealed increased expression of FGFR1 in osteoclasts during differentiation. Therefore, studies were performed to determine whether tumor cell-derived FGFs are capable of promoting osteoclast differentiation and activity. Using both non-transformed and transformed cell lines, we demonstrate that breast cancer cells express a number of FGF ligands that are known to activate FGFR1. Furthermore our results demonstrate that inhibition of FGFR activity using the clinically relevant inhibitor BGJ398 leads to reduced osteoclast differentiation and activity in vitro. Treatment of mice injected with tumor cells into the femurs with BGJ398 leads to reduced osteoclast activity and bone destruction. Together, these studies demonstrate that tumor cell-derived FGFs enhance osteoclast function and contribute to the formation of metastatic lesions in breast cancer.
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影响因子：
4.8
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