Anjanappa Manjushree, Burnett Riesa, Zieger Michael A, Merfeld-Clauss Stephanie, Wooden William, March Keith, Tholpady Sunil, Nakshatri Harikrishna
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. Richard L Roudebush VA Medical Center, Indianapolis, Indiana.
Mol Cancer Res. 2016 Jul;14(7):660-71. doi: 10.1158/1541-7786.MCR-16-0055. Epub 2016 Apr 20.
Adipose-derived stem cells (ASC) have received considerable attention in oncology because of the known direct link between obesity and cancer as well as the use of ASCs in reconstructive surgery after tumor ablation. Previous studies have documented how cancer cells commandeer ASCs to support their survival by altering extracellular matrix composition and stiffness, migration, and metastasis. This study focused on delineating the effects of ASCs and adipocytes on the self-renewal of stem/progenitor cells and hierarchy of breast epithelial cells. The immortalized breast epithelial cell line MCF10A, ductal carcinoma in situ (DCIS) cell lines MCF10DCIS.com and SUM225, and MCF10A-overexpressing SRC oncogene were examined using a mammosphere assay and flow cytometry for the effects of ASCs on their self-renewal and stem-luminal progenitor-differentiated cell surface marker profiles. Interestingly, ASCs promoted the self-renewal of all cell types except SUM225. ASC coculture or treatment with ASC conditioned media altered the number of CD49f(high)/EpCAM(low) basal/stem-like and CD49f(medium)/EpCAM(medium) luminal progenitor cells. Among multiple factors secreted by ASCs, IFNγ and hepatocyte growth factor (HGF) displayed unique actions on epithelial cell hierarchy. IFNγ increased stem/progenitor-like cells while simultaneously reducing the size of mammospheres, whereas HGF increased the size of mammospheres with an accompanying increase in luminal progenitor cells. ASCs expressed higher levels of HGF, whereas adipocytes expressed higher levels of IFNγ. As luminal progenitor cells are believed to be prone for transformation, IFNγ and HGF expression status of ASCs may influence susceptibility for developing breast cancer as well as on outcomes of autologous fat transplantation on residual/dormant tumor cells.
This study suggests that the ratio of ASCs to adipocytes influences cancer cell hierarchy, which may impact incidence and progression. Mol Cancer Res; 14(7); 660-71. ©2016 AACR.
脂肪来源干细胞（ASC）在肿瘤学领域受到了广泛关注，这是因为肥胖与癌症之间存在已知的直接联系，以及ASC在肿瘤切除后的重建手术中的应用。先前的研究记录了癌细胞如何通过改变细胞外基质的组成和硬度、迁移和转移来征用ASC以支持其存活。本研究聚焦于描绘ASC和脂肪细胞对乳腺上皮干细胞/祖细胞自我更新及细胞层级的影响。使用乳腺球形成试验和流式细胞术，检测永生化乳腺上皮细胞系MCF10A、原位导管癌（DCIS）细胞系MCF10DCIS.com和SUM225，以及过表达SRC癌基因的MCF10A，以研究ASC对其自我更新和干细胞-管腔祖细胞-分化细胞表面标志物谱的影响。有趣的是，ASC促进了除SUM225外所有细胞类型的自我更新。ASC共培养或用ASC条件培养基处理改变了CD49f（高）/EpCAM（低）基底/干细胞样和CD49f（中）/EpCAM（中）管腔祖细胞的数量。在ASC分泌的多种因子中，IFNγ和肝细胞生长因子（HGF）对上皮细胞层级表现出独特作用。IFNγ增加了干细胞/祖细胞样细胞，同时减小了乳腺球的大小，而HGF增加了乳腺球的大小，同时管腔祖细胞数量增加。ASC表达较高水平的HGF，而脂肪细胞表达较高水平的IFNγ。由于管腔祖细胞被认为易于发生转化，ASC的IFNγ和HGF表达状态可能会影响患乳腺癌的易感性以及自体脂肪移植对残留/休眠肿瘤细胞的影响。
本研究表明ASC与脂肪细胞的比例影响癌细胞层级，这可能会影响发病率和进展。《分子癌症研究》；14(7)；660 - 71。©2016美国癌症研究协会。
