Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer
Polyploid Adipose Stem Cells Shift the Balance of IGF1/IGFBP2 to Promote the Growth of Breast Cancer
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DOI：
10.3389/fonc.2020.00157
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发表时间：
2020-02-18
影响因子：
4.7
通讯作者：
Katona, Robert L.
中科院分区：
文献类型：
--
作者：
Fajka-Boja, Roberta;Szebeni, Gabor J.;Katona, Robert L.
背景：脂肪组织和乳腺上皮细胞的紧密接触使脂肪细胞易于参与乳腺癌的发生。脂肪组织干细胞（ASC）有助于肿瘤基质并促进癌细胞的生长。在我们以前的研究中，我们已经证明，在长期体外培养过程中经历多倍化的小鼠ASCs以IGF 1依赖的方式促进4T1小鼠乳腺癌细胞的增殖。目的：在本研究中，我们的目的是阐明ASC-derived IGF 1的调节。方法：将4T1鼠乳腺癌细胞与内脏脂肪来源的ASC（vASC）或与多倍体ASC.B6细胞系共移植到雌性BALB/c小鼠中，并监测肿瘤生长和肺转移。对vASC和ASC.B6细胞的条件培养基进行LC-MS/MS分析，并通过Western印迹验证IGFBP2的产生。通过向ASC.B6和4T1的共培养物中添加重组IGFBP2来检查调节作用。结果：与正常核型的vASCs相比，多倍体ASCs对肿瘤的生长和转移有更强的促进作用。vASC产生IGF1调节因子IGFBP2，其抑制4T1细胞的增殖。通过ASCs的多倍化和IGF1分泌的增强下调IGFBP2允许在4T1细胞中的生存信号传导，导致Akt磷酸化。结论：我们的结果暗示，在肿瘤微环境中的ASCs通过IGF/IGFBP系统主动调节乳腺癌细胞的生长。
Background: The close proximity of adipose tissue and mammary epithelium predispose involvement of adipose cells in breast cancer development. Adipose-tissue stem cells (ASCs) contribute to tumor stroma and promote growth of cancer cells. In our previous study, we have shown that murine ASCs, which undergo polyploidization during their prolonged in vitro culturing, enhanced the proliferation of 4T1 murine breast cancer cells in IGF1 dependent manner.Aims: In the present study, our aim was to clarify the regulation of ASC-derived IGF1.Methods: 4T1 murine breast carcinoma cells were co-transplanted with visceral fat-derived ASCs (vASC) or with the polyploid ASC.B6 cell line into female BALB/c mice and tumor growth and lung metastasis were monitored. The conditioned media of vASCs and ASC.B6 cells were subjected to LC-MS/MS analysis and the production of IGFBP2 was verified by Western blotting. The regulatory effect was examined by adding recombinant IGFBP2 to the co-culture of ASC.B6 and 4T1. Akt/protein kinase B (PKB) activation was detected by Western blotting.Results: Polyploid ASCs promoted the tumor growth and metastasis more potently than vASCs with normal karyotype. vASCs produced the IGF1 regulator IGFBP2, which inhibited proliferation of 4T1 cells. Downregulation of IGFBP2 by polyploidization of ASCs and enhanced secretion of IGF1 allowed survival signaling in 4T1 cells, leading to Akt phosphorylation.Conclusions: Our results implicate that ASCs in the tumor microenvironment actively regulate the growth of breast cancer cells through the IGF/IGFBP system.