Three-Dimensional Mechanical Loading Modulates the Osteogenic Response of Mesenchymal Stem Cells to Tumor-Derived Soluble Signals

Abstract

Dynamic mechanical loading is a strong anabolic signal in the skeleton, increasing osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) and increasing the bone-forming activity of osteoblasts, but its role in bone metastatic cancer is relatively unknown. In this study, we integrated a hydroxyapatite-containing three-dimensional (3D) scaffold platform with controlled mechanical stimulation to investigate the effects of cyclic compression on the interplay between breast cancer cells and BM-MSCs as it pertains to bone metastasis. BM-MSCs cultured within mineral-containing 3D poly(lactide-co-glycolide) (PLG) scaffolds differentiated into mature osteoblasts, and exposure to tumor-derived soluble factors promoted this process. When BM-MSCs undergoing osteogenic differentiation were exposed to conditioned media collected from mechanically loaded breast cancer cells, their gene expression of osteopontin was increased. This was further enhanced when mechanical compression was simultaneously applied to BM-MSCs, leading to more uniformly deposited osteopontin within scaffold pores. These results suggest that mechanical loading of 3D scaffold-based culture models may be utilized to evaluate the role of physiologically relevant physical cues on bone metastatic breast cancer. Furthermore, our data imply that cyclic mechanical stimuli within the bone microenvironment modulate interactions between tumor cells and BM-MSCs that are relevant to bone metastasis.

Perfusion applied to a 3D model of bone metastasis results in uniformly dispersed mechanical stimuli

“…Tissue engineering strategies can also be leveraged to elucidate the effects of mechanical stimuli in bone metastasis, including delineating the relative effects of matrix deformation and fluid flow. When compression was applied to a fluid‐filled, porous 3D model of bone metastasis, breast cancer cell expression of osteolytic genes was reduced and signaling with osteoblasts was altered (Lynch et al, , ). In primary breast cancer, mechanical cues also modulate cancer cell behavior.…”

Biomimetic strategies to recapitulate organ specific microenvironments for studying breast cancer metastasis

“…Mineralized scaffolds closely mimic the vicious interaction between osteoblasts and BCC resulting in bone matrix resorption. Notably, the BCCs were found to be more susceptible to bisphosphonate treatment on mineralized scaffolds in the presence of osteoblasts . While these techniques incorporate the effects of HA in the bone ECM and provide key insights into interactions of BCCs with BMSCs in a mineralized environment, they are unable to capture the vicious cycle of bone metastasis due to limited culture time of 7–10 days because of early attainment of confluency and low matrix stability.…”

Engineering 3D Models of Tumors and Bone to Understand Tumor-Induced Bone Disease and Improve Treatments

“…One such study employed HA-containing PLGA scaffolds under cyclic compression to investigate the interactions between MDA-MB-231 breast cancer cells and human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in the mechanically stressed environment [80•]. Before investigating mechanical loading, HA-containing scaffolds were seeded with hBM-MSCs and treated with tumor-conditioned media to observe how tumor-derived soluble factors influence osteogenic behavior.…”