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.

New 3D-Culture Approaches to Study Interactions of Bone Marrow Adipocytes with Metastatic Prostate Cancer Cells

“…There is a great need for in vitro 3D models that can address the complexity of the bone tumor microenvironment, yet allow dissection of the mechanisms behind the contribution of specific cell types to the metastatic growth. There has been a growing effort to generate 3D models that would represent a bridge between the 2D monolayer cultures and in vivo tumor microenvironment, with the idea of capturing the physiological complexity, multiplicity of cell types, ECM composition, and temporal and spatial distribution of soluble factors in the bone microenvironment ( 21 , 28 , 58 – 61 ). Many of these models have been key to demonstrating the importance of 3D tumor architecture in mechanistic understanding of basic cancer biology and, especially, in evaluating tumor response to therapy ( 22 , 58 , 61 ).…”

“…Three-dimensional, multi-cellular cell culture models have become well-accepted tools for dissecting complex molecular mechanisms of tumor progression that may not be possible to dissect in vivo . There have also been many advancements in the development of 3D culture systems that mimic specific tumor niches, including very complex and dynamic microenvironments such as bone ( 28 ). Models intended to interrogate the mechanisms of skeletal metastases range from culture of tumor cells and specific bone-derived cells on biologically derived or synthetic matrices, through the use of patient-derived xenografts and direct culture of tumor cells with bone explants ( 21 , 28 ).…”

“…There have also been many advancements in the development of 3D culture systems that mimic specific tumor niches, including very complex and dynamic microenvironments such as bone ( 28 ). Models intended to interrogate the mechanisms of skeletal metastases range from culture of tumor cells and specific bone-derived cells on biologically derived or synthetic matrices, through the use of patient-derived xenografts and direct culture of tumor cells with bone explants ( 21 , 28 ). However, aside from one recently reported in vitro system designed to evaluate bone marrow adipose colonization by breast cancer cells ( 6 ), there have been no in vitro 3D models that consider involvement of marrow adipocytes.…”

Design of spherically structured 3D in vitro tumor models -Advances and prospects

“…Silk fibroin, has also been extensively used for the development of 3D in vitro models, particularly for the study of cancer-to-bone metastasis [120,121], due to its resistance to protease degradation, as well as mechanical and cell adhesion properties (e.g., resultant from the naturally occurring RGD sequences of the fibroin protein). Adding to this silk fibroin can also be conjugated with different biomolecular cues (e.g., BMP-2, EGFR, SDF-1) [142,143]. To date, these scaffolds have been used for establishing in vitro 3D models of primary tumors including those of prostate [85], and osteosarcoma [122].…”

Novel and Conventional Preclinical Models to Investigate Bone Metastasis

“…Many in vitro approaches to study bone metastasis are summarized in a systematic review by Salamanna and colleagues [37] and by Krishnan and colleagues [38]. Marlow and colleagues have established an in vitro dormancy model with a co-culture of breast cancer cells and bone cells, and identified factors that keep cells in proliferatory or inhibitory (dormant) states [39].…”