Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis
Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis
复制标题
DOI：
10.1038/onc.2015.297
复制
发表时间：
2016-05-05
期刊：
影响因子：
8
通讯作者：
Li, X.
中科院分区：
文献类型：
--
作者：
Meng, X.;Vander Ark, A.;Li, X.
乳腺癌（BCa）骨转移引起骨溶解性病变，这是由于转移的BCa细胞与破骨细胞和成骨细胞相互作用的结果。破骨细胞从髓系细胞分化而来。为了了解转化生长因子β (tgf - β)在骨髓谱系中的细胞特异性作用，在BCa骨转移中，将MDA-MB-231 BCa细胞胫骨内或心脏内注射到LysM(Cre)/Tgfbr2（floxE2/floxE2）敲除（LysM(Cre)/Tgfbr2 KO）或Tgfbr2（floxE2/floxE2）小鼠中。通过对病灶数量和面积的分析，比较骨转移病灶的发展情况。我们发现，在心脏和胫骨注射模型中，LysM(Cre)/Tgfbr2敲除显著降低MDA-MB-231骨病变的发展。LysM(Cre)/Tgfbr2敲除抑制转移骨肿瘤细胞增殖、血管生成和破骨细胞生成。细胞因子阵列分析显示，在mda - mb -231注射的LysM(Cre)/Tgfbr2 KO小鼠胫骨中，碱性成纤维细胞生长因子（bFGF）下调，重组bFGF静脉注射到LysM(Cre)/Tgfbr2 KO小鼠可恢复被抑制的转移性骨病变的发展。bFGF挽救骨病变的机制是通过与FGF受体1 （FGFR1）结合后，通过下游的丝裂原活化蛋白激酶(MAPK)-细胞外信号调节激酶(ERK)-cFos途径促进肿瘤细胞增殖。与动物研究一致，我们发现在人BCa骨转移组织中，tgf - β II型受体（T β RII）和p-Smad2在破骨细胞和肿瘤细胞中表达，并且与FGFR1的表达相关。我们的研究表明骨髓特异性tgf - β信号介导的骨内bFGF促进BCa骨转移。
Breast cancer (BCa) bone metastases cause osteolytic bone lesions, which result from the interactions of metastatic BCa cells with osteoclasts and osteoblasts. Osteoclasts differentiate from myeloid lineage cells. To understand the cell-specific role of transforming growth factor beta (TGF-beta) in the myeloid lineage, in BCa bone metastases, MDA-MB-231 BCa cells were intra-tibially or intra-cardially injected into LysM(Cre)/Tgfbr2(floxE2/floxE2) knockout (LysM(Cre)/Tgfbr2 KO) or Tgfbr2(floxE2/floxE2) mice. Metastatic bone lesion development was compared by analysis of both lesion number and area. We found that LysM(Cre)/Tgfbr2 knockout significantly decreased MDA-MB-231 bone lesion development in both the cardiac and tibial injection models. LysM(Cre)/Tgfbr2 knockout inhibited the tumor cell proliferation, angiogenesis and osteoclastogenesis of the metastatic bones. Cytokine array analysis showed that basic fibroblast growth factor (bFGF) was downregulated in MDA-MB-231-injected tibiae from the LysM(Cre)/Tgfbr2 KO group, and intravenous injection of the recombinant bFGF to LysM(Cre)/Tgfbr2 KO mice rescued the inhibited metastatic bone lesion development. The mechanism by which bFGF rescued the bone lesion development was by promotion of tumor cell proliferation through the downstream mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-cFos pathway after binding to the FGF receptor 1 (FGFR1). Consistent with animal studies, we found that in human BCa bone metastatic tissues, TGF-beta type II receptor (T beta RII) and p-Smad2 were expressed in osteoclasts and tumor cells, and were correlated with the expression of FGFR1. Our studies suggest that myeloid-specific TGF-beta signaling-mediated bFGF in the bone promotes BCa bone metastasis.