A systematic review on in vitro 3D bone metastases models: A new horizon to recapitulate the native clinical scenario?

Abstract

While the skeleton is not the only organ where metastasis can occur, it is one of the preferred sites, with a significant impact in patients' quality of life. With the aim of delineating the cellular and molecular mechanisms of bone metastasis, numerous studies have been employed to identify any contributing factors that trigger cancer progression. One of the major limitations of studying cancer-bone metastasis is the multifaceted nature of the native bone environment and the lack of reliable, simple, and not expensive models that strictly mimic the biological processes occurring in vivo allowing a correct translation of results. Currently, with the growing acceptance of in vitro models as effective tools for studying cancer biology, three-dimensional (3D) models have emerged as a compromise between two-dimensional cultures of isolated cancer cells and the complexity of human cancer xenografts in immunocompromised animal hosts. This descriptive systematic literature review summarizes the current status of advanced and alternative 3D in vitro bone metastases models. We have also reviewed the strategies employed by researchers to set-up these models with special reference to recent promising developments trying to better replicate the complexity and heterogeneity of a human metastasis in situ, with an outlook at their use in medicine. All these aspects will greatly contribute to the existing knowledge on bone metastases, providing a specific link to clinical scenarios and thus making 3D in vitro bone metastasis models an attractive tool for multidisciplinary experts.

Keywords: 3D in vitro model; bone metastases; cancer cells; metastatic microenvironment; systematic literature review.

Figure 1. Systematic literature review flow diagram

Figure 2. Historical distribution of 3D bone metastases in vitro model works according to the year of publication

Figure 3

A. Pie chart of bone metastases studies that considered different 3D models: device-assisted assembly, matrix-assisted assembly and direct bone-tumor cell contact. B. Pie chart of the number of studies using natural or synthetic matrices.

Figure 4. Schematic representation of the different 3D models of bone metastasis emerging from this review: device-assisted assembly models, matrix-assisted assembly models and direct bone-tumor cell contact models

Figure 5. Cancer cell type used to set-up 3D bone metastasis models