1 Department of Pathology, University of Cambridge , Cambridge, United Kingdom .
2 Cancer Research UK Cambridge Institute, University of Cambridge , Cambridge, United Kingdom .
Tissue Eng Part A. 2018 Sep;24(17-18):1309-1319. doi: 10.1089/ten.TEA.2017.0509. Epub 2018 Jul 3.
Adipocytes are one of the major stromal cell components of the human breast. These cells play a key role in the development of the gland and are implicated in breast tumorigenesis. Frequently, directional stromal collagen I fibers are found surrounding aggressive breast tumors. These fibers enhance breast cancer cell migration and are associated with poor patient prognosis. We sought to recapitulate these stromal components in vitro to provide a three-dimensional (3D) model comprising human adipose tissue and anisotropic collagen fibers. We developed a human mesenchymal stem cell (hMSC) cell line capable of undergoing differentiation into mature adipocytes by immortalizing hMSCs, isolated from breast reduction mammoplasties, through retroviral transduction. These immortalized hMSCs were seeded in engineered collagen I scaffolds with directional internal architecture, and adipogenesis was chemically induced, resulting in human adipose tissue being synthesized in vitro in an architectural structure associated with breast tumorigenesis. Subsequently, fluorescently labeled cells from an established breast cancer cell line were seeded into this model, cocultured for 7 days and imaged using multiphoton microscopy. Enhanced breast cancer cell migration was observed in the adipose-containing model over empty scaffold controls, demonstrating an adipocyte-mediated influence on breast cancer cell migration. Thus, this 3D in vitro model recapitulates the migratory effects of adipocytes observed on breast cancer cells and suggests that it could have utility with fresh breast tumor biopsies as an assay for cancer therapeutic efficacy in personalized medicine strategies.
脂肪细胞是人类乳腺的主要基质细胞成分之一。这些细胞在乳腺的发育中起着关键作用，并与乳腺癌的发生有关。通常，在侵袭性乳腺癌周围可以发现定向的基质胶原 I 纤维。这些纤维增强了乳腺癌细胞的迁移，并与患者预后不良相关。我们试图在体外重现这些基质成分，提供一个包含人类脂肪组织和各向异性胶原纤维的三维（3D）模型。我们通过逆转录病毒转导，从乳房缩小成形术中分离出人骨髓间充质干细胞（hMSC），通过永生化 hMSC 来开发能够分化为成熟脂肪细胞的 hMSC 细胞系。这些永生化的 hMSC 被接种在具有定向内部结构的工程胶原 I 支架上，并通过化学诱导进行脂肪生成，从而在体外合成与乳腺癌发生相关的结构的人脂肪组织。随后，将来自已建立的乳腺癌细胞系的荧光标记细胞接种到该模型中，共培养 7 天，并使用多光子显微镜进行成像。在含有脂肪的模型中观察到乳腺癌细胞的迁移增强，表明脂肪细胞对乳腺癌细胞迁移有影响。因此，这种 3D 体外模型再现了在乳腺癌细胞上观察到的脂肪细胞的迁移效应，并表明它可能对新鲜的乳腺癌活检具有实用性，作为个性化医疗策略中癌症治疗效果的检测。
