Regenerative Medicine Technologies Laboratory, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland.
Biocompatibility and Cell Culture Laboratory 'BioCell', Department of Chemistry, Materials and Chemical Engineering 'Giulio Natta', Politecnico di Milano, 20133 Milano, Italy.
Biofabrication. 2021 Apr 26;13(3). doi: 10.1088/1758-5090/abefea.
Bone metastases occur in 65%-80% advanced breast cancer patients. Although significant progresses have been made in understanding the biological mechanisms driving the bone metastatic cascade, traditional 2Dmodels and animal studies are not effectively reproducing breast cancer cells (CCs) interactions with the bone microenvironment and suffer from species-specific differences, respectively. Moreover, simplifiedmodels cannot realistically estimate drug anti-tumoral properties and side effects, hence leading to pre-clinical testing frequent failures. To solve this issue, a 3D metastatic bone minitissue (MBm) is designed with embedded human osteoblasts, osteoclasts, bone-resident macrophages, endothelial cells and breast CCs. This minitissue recapitulates key features of the bone metastatic niche, including the alteration of macrophage polarization and microvascular architecture, along with the induction of CC micrometastases and osteomimicry. The minitissue reflects breast CC organ-specific metastatization to bone compared to a muscle minitissue. Finally, two FDA approved drugs, doxorubicin and rapamycin, have been tested showing that the dose required to impair CC growth is significantly higher in the MBm compared to a simpler CC monoculture minitissue. The MBm allows the investigation of metastasis key biological features and represents a reliable tool to better predict drug effects on the metastatic bone microenvironment.
骨转移发生在 65%-80%的晚期乳腺癌患者中。尽管在理解驱动骨转移级联反应的生物学机制方面已经取得了重大进展，但传统的 2D 模型和动物研究不能有效地再现乳腺癌细胞（CCs）与骨微环境的相互作用，分别存在物种特异性差异。此外，简化模型不能真实估计药物的抗肿瘤特性和副作用，因此导致临床前测试频繁失败。为了解决这个问题，设计了一种带有嵌入式人成骨细胞、破骨细胞、骨驻留巨噬细胞、内皮细胞和乳腺癌 CCs 的 3D 转移性骨微组织（MBm）。这种微组织再现了骨转移龛的关键特征，包括巨噬细胞极化和微血管结构的改变，以及 CC 微转移和骨模拟的诱导。与肌肉微组织相比，微组织反映了乳腺癌 CC 器官特异性向骨转移。最后，测试了两种已获 FDA 批准的药物，多柔比星和雷帕霉素，结果表明，与更简单的 CC 单核培养微组织相比，在 MBm 中抑制 CC 生长所需的剂量明显更高。MBm 允许研究转移的关键生物学特征，并代表一种可靠的工具，可以更好地预测药物对转移性骨微环境的影响。
