Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
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.
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Acknowledgements
We thank the research core facility of west china hospital at Sichuan university for assistance with histopathology.
Funding
This work was supported by grants from the National Natural Science Foundation of China (nos. 81770875, 81572639), the Science and Technology Department of Sichuan Province (2018SZ0142), the Sichuan University (no. 2018SCUH0093), and the National Clinical Research Center for Geriatrics of West China Hospital (no. Z2018B05), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (2020HXFH008, ZYGD18022).
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GL and MT: methodology, investigation, formal analysis, writing—original draft preparation; QZ, LL, YL, YX and CL: methodology, investigation, data curation, formal analysis; LT and XC: writing—original draft preparation, methodology, visualization; XY: conceptualization, writing—original draft preparation, writing—review and editing, visualization, supervision, project administration, funding acquisition. GL and MT contributed equally to this article.
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All procedures were approved by the Institutional Animal Care and Use Committee of West China Hospital, Sichuan University.
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Luo, G., Tang, M., Zhao, Q. et al. Bone marrow adipocytes enhance osteolytic bone destruction by activating 1q21.3(S100A7/8/9-IL6R)-TLR4 pathway in lung cancer. J Cancer Res Clin Oncol 146, 2241–2253 (2020). https://doi.org/10.1007/s00432-020-03277-9
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DOI: https://doi.org/10.1007/s00432-020-03277-9