Engineering a biomimetic three-dimensional nanostructured bone model for breast cancer bone metastasis study

Abstract

Traditional breast cancer (BrCa) bone metastasis models contain many limitations with regards to controllability, reproducibility and flexibility of design. In this study, a novel biomimetic bone microenvironment was created by integrating hydroxyapatite (HA) and native bioactive factors deposited by osteogenic induction of human bone marrow mesenchymal stem cells (MSCs) within a cytocompatible chitosan hydrogel. It was found that a 10% nanocrystalline HA (nHA) chitosan scaffold exhibited the highest BrCa adhesion and proliferation when compared to chitosan scaffolds with 20% nHA, 10% and 20% microcrystalline HA as well as amorphous HA. This 3-D tunable bone scaffold can provide a biologically relevant environment, increase cell–cell and cell–matrix interactions as found in native bone, and retain the behavior of BrCa cells with different metastasis potential (i.e. highly metastatic MDA-MB-231, less metastatic MCF-7 and transfected MDA-MB-231). The co-culture of MSCs and MDA-MB-231 in this bone model illustrated that MSCs have the capacity to upregulate the expression of the well-known metastasis-associated gene metadherin within BrCa cells. In summary, this study illustrates the ability of our 3-D bone model to create a biomimetic environment conducive to recapitulating the behavior of metastatic BrCa cells, making it a promising tool for in vitro BrCa cell bone metastasis study and for the discovery of potential therapeutics.