Modeling the Human Bone-Tumor Niche: Reducing and Replacing the Need for Animal Data

Abstract

Bone is the most common site for cancer metastasis. Understanding the interactions within the complex, heterogeneous bone-tumor microenvironment is essential for the development of new therapeutics. Various animal models of tumor-induced bone disease are routinely used to provide valuable information on the relationship between cancer cells and the skeleton. However, new model systems exist that offer an alternative approach to the use of animals and might more accurately reveal the cellular interactions occurring within the human bone-tumor niche. This review highlights replacement models that mimic the bone microenvironment and where cancer metastases and tumor growth might be assessed alongside bone turnover. Such culture models include the use of calcified regions of animal tissue and scaffolds made from bone mineral hydroxyapatite, synthetic polymers that can be manipulated during manufacture to create structures resembling trabecular bone surfaces, gel composites that can be modified for stiffness and porosity to resemble conditions in the tumor-bone microenvironment. Possibly the most accurate model system involves the use of fresh human bone samples, which can be cultured ex vivo in the presence of human tumor cells and demonstrate similar cancer cell-bone cell interactions as described in vivo. In addition, the use of mathematical modeling and computational biology approaches provide an alternative to preliminary animal testing. The use of such models offers the capacity to mimic significant elements of the human bone-tumor environment, and complement, refine, or replace the use of preclinical models. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Keywords: ANIMAL MODELS; BONE MODELING; BONE REMODELING; CANCER; TUMOR‐INDUCED BONE DISEASE.

Figure 1

Summary models for animal replacement in modeling the tumor–bone niche. The computational modeling and inclusion of tumor cells in synthetic and organic hard and soft matrices, including human bone and local host cells, offers alternate approaches to the use of animals in the study of cancer–bone disease.

Figure 2

Ex vivo human bone–tumor cell niche. Viable enhanced green fluorescent protein‐ (EGFP‐) tagged PC3 tumor cells (green) and mcherry‐labeled HS5 stromal cells (red) are visualized equally live on 2D plastic surface (A, scale bar = 200 μm) and live in situ within the human bone core assay (B, scale bar = 200 μm). Viable normal bone matrix and marrow networks are visible following culture up to day 14 (C, scale bar = 500 μm), allowing for the continued growth of niche populations including adipocytes (black arrows) and vascular components (C, green arrows) and the propagation of inoculated tumor cells adhering and proliferation upon and within bone (blue arrows) (D, scale bar = 200 μm) (H&E‐orange G), and confirmation of EGFP tumor cells interacting with bone cells of the host tissue by immunofluorescent staining (E, F, scale bar = 50 μm).