Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, South Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, South Korea; Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 03080, South Korea.
Biomaterials. 2021 Feb;269:120622. doi: 10.1016/j.biomaterials.2020.120622. Epub 2020 Dec 21.
Although obesity is a newly considered risk factor for cancer, the mechanisms by which adipocyte-derived metabolites accelerate cancer malignancy have yet to be elucidated. To identify the connection among heterogeneous cell types, conventional methods including Transwell assays or conditioned media (CM) have been used; however, these methods do not fully reflect niche effects in the tumor microenvironment (TME). Here, we established an oxygen permeable polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture system to allow direct attachment between human adipocyte derived stem cells (ADSCs) and cancer cells. By doing so, a physiologically bioactive TME was created, which could be used to reveal further the relationships between different cell types. We found that co-culture of cancer cells with ADSCs resulted in a dispersion phenomenon, and the dispersed spheroid was well matched with the enhanced metastatic potential of cancer cells. Lipid profiling and in vitro migration assays suggested that lipids are the driving force for cancer cell migration via HIF-1α upregulation. In addition, the lipid/HIF-1α axis promoted tumor metastasis in a xenograft mouse model. This study presents an in vitro model of a biomimetic TME and provides new mechanistic insights into the effects of ADSC-released fatty acids on cancer cells as oncometabolites.
虽然肥胖已被新认为是癌症的一个风险因素，但脂肪细胞衍生代谢物加速癌症恶性进展的机制尚不清楚。为了鉴定不同细胞类型之间的联系，传统方法包括 Transwell 检测或条件培养基（CM）已被使用；然而，这些方法并不能完全反映肿瘤微环境（TME）中的龛位效应。在这里，我们建立了一个氧通透的聚二甲基硅氧烷（PDMS）为基础的三维（3D）培养系统，允许人脂肪来源干细胞（ADSCs）和癌细胞直接附着。通过这样做，创建了一个具有生理生物活性的 TME，可以进一步揭示不同细胞类型之间的关系。我们发现，癌细胞与 ADSCs 的共培养导致了分散现象，而分散的球体与癌细胞增强的转移潜能相匹配。脂质分析和体外迁移实验表明，脂质通过 HIF-1α 的上调是癌细胞迁移的驱动力。此外，脂质/HIF-1α 轴在异种移植小鼠模型中促进了肿瘤转移。本研究提出了一个仿生 TME 的体外模型，并为 ADSC 释放的脂肪酸作为致癌代谢物对癌细胞的影响提供了新的机制见解。
