Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Department of General Practice, West China Hospital, Sichuan University, Chengdu, China.
J Cancer Res Clin Oncol. 2020 Sep;146(9):2241-2253. doi: 10.1007/s00432-020-03277-9. Epub 2020 Jun 3.
Bone metastasis is the result of complex crosstalk between tumor cells and bone marrow cells. Bone marrow adipocytes (BMAs) are the most abundant cell type in adult bone marrow. Therefore, we explore the effects of BMAs on bone metastasis in lung cancer.
RNA-seq was used to compare the mRNA expression level of bone metastatic SBC5 cells and non-bone metastatic SBC3 cells. Rosiglitazone-induced marrow adiposity and intra-femoral injection of SBC5 cells were used to demonstrate the relationship between BMAs and SBC5 cells in vivo. Co-culture system, gene co-expression, gene ontology (GO) enrichment analysis and protein-protein interaction (PPI) network were used to explore the potential mechanism.
BMAs specially enhance the invasion of bone metastatic SBC5 instead of non-bone metastatic SBC3 in vitro. SBC5 instead of SBC3 promoted osteoblast and osteoclast differentiation as well as de-differentiation of mature BMAs. Rosiglitazone-induced marrow adiposity significantly enhanced osteolytic lesion induced by SBC5 in vivo. RNA-seq revealed that compared with SBC3, S100A9 and S100A8 genes were the most prominent genes up-regulated in SBC5 cells. High expression of S100A8/9 in SBC5 could be responsible for the crosstalk between lung cancer cells and BMAs. More importantly, interleukin 6 receptor (IL6R), which is adjacent to S100A8/A9 in 1q21.3, was significantly up-regulated by BMAs in vitro. S100A8/A9 (1 μg/ml) could obviously enhance the osteoblastic differentiation and inhibit adipogenic differentiation, whereas TLR4 inhibitor TAK242 (10 μmol/l) significantly attenuated this effect.
Our study suggested that bone marrow adipocyte may communicate with lung cancer cells via 1q21.3 (S100A8/A9-IL6R)-TLR4 pathway to promote osteolytic bone destruction. 1q21.3 (S100A8/A9-IL6R) is a potential target for the treatment of lung cancer bone metastasis.
骨转移是肿瘤细胞与骨髓细胞之间复杂串扰的结果。骨髓脂肪细胞（BMAs）是成人体内骨髓中最丰富的细胞类型。因此，我们探讨了 BMAs 对肺癌骨转移的影响。
采用 RNA-seq 比较骨转移 SBC5 细胞和非骨转移 SBC3 细胞的 mRNA 表达水平。使用罗格列酮诱导骨髓脂肪增多和股骨内注射 SBC5 细胞，在体内证明 BMAs 与 SBC5 细胞之间的关系。共培养系统、基因共表达、基因本体（GO）富集分析和蛋白质-蛋白质相互作用（PPI）网络用于探索潜在的机制。
BMAs 特异性增强了骨转移 SBC5 而非非骨转移 SBC3 的体外侵袭。SBC5 而非 SBC3 促进成骨细胞和破骨细胞分化以及成熟 BMAs 的去分化。罗格列酮诱导的骨髓脂肪增多显著增强了 SBC5 在体内引起的溶骨性病变。RNA-seq 显示，与 SBC3 相比，S100A9 和 S100A8 基因在 SBC5 细胞中上调最为显著。SBC5 中 S100A8/9 的高表达可能是肺癌细胞与 BMAs 之间串扰的原因。更重要的是，白细胞介素 6 受体（IL6R）在 1q21.3 与 S100A8/A9 相邻，在体外 BMAs 明显上调。S100A8/A9（1μg/ml）可明显增强成骨细胞分化，抑制脂肪细胞分化，而 TLR4 抑制剂 TAK242（10μmol/L）显著减弱了这种作用。
我们的研究表明，骨髓脂肪细胞可能通过 1q21.3（S100A8/A9-IL6R）-TLR4 途径与肺癌细胞通讯，促进溶骨性骨破坏。1q21.3（S100A8/A9-IL6R）是治疗肺癌骨转移的潜在靶点。
