Abstract
Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated bone destruction and inhibition of repair. The resultant so-called osteolytic lesions (OL) take the form of tumor-filled cavities in bone that cause pain, fractures, and associated morbidity. Furthermore, the OL microenvironment can support survival of tumor cells and resistance to chemotherapy. Therefore, a deeper understanding of OL formation and MBD progression is imperative for the development of future therapeutic strategies. Herein, we describe a novel in vitro platform to study bone–tumor interactions based on three-dimensional co-culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) in a rotating wall vessel bioreactor (RWV) while attached to micro-carrier beads coated with extracellular matrix (ECM) composed of factors found in anabolic bone tissue. Osteoinhibition was recapitulated in this model by co-culturing the OEhMSCs with a bone–tumor cell line (MOSJ-Dkk1) that secretes the canonical Wnt (cWnt) inhibitor Dkk-1, a tumor-borne osteoinhibitory factor widely associated with several forms of MBD, or intact tumor fragments from Dkk-1 positive patient-derived xenografts (PDX). Using the model, we observed that depending on the conditions of growth, tumor cells can biochemically inhibit osteogenesis by disrupting cWnt activity in OEhMSCs, while simultaneously co-engrafting with OEhMSCs, displacing them from the niche, perturbing their activity, and promoting cell death. In the absence of detectable co-engraftment with OEhMSCs, Dkk-1 positive PDX fragments had the capacity to enhance OEhMSC proliferation while inhibiting their osteogenic differentiation. The model described has the capacity to provide new and quantifiable insights into the multiple pathological mechanisms of MBD that are not readily measured using monolayer culture or animal models.
Highlights
40% of newly diagnosed cancers per year in the US will involve bone, disrupting bone turnover and causing catastrophic damage in the form of osteolytic lesions (OLs)[1]
Culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) and MOSJ OS cells in the rotating wall vessel bioreactor (RWV) on collagen I-coated beads OEhMSCs from human bone marrow were selected to mimic the osteogenic niche because the cells undergo osteogenesis in vivo[28,30,36,37]
Growth of OEhMCSs in the RWV represented an effective solution because OEhMSCs have been shown to regenerate bone in vivo[30,36] and RWVs have the potential to support large 3D structures[18,19]
Summary
40% of newly diagnosed cancers per year in the US will involve bone, disrupting bone turnover and causing catastrophic damage in the form of osteolytic lesions (OLs)[1]. OLs cause serious fractures and untenable pain, but more importantly, they provide a niche for tumor propagation, reducing the probability of survival[2]. OLs become persistent hotspots for drugresistant cell selection and refractory disease[3,4,5,6,7]. It is Official journal of the Cell Death Differentiation Association. While priority is given to reducing tumor load and preventing relapse, promoting repair of OLs is important given that OLs provide an ideal environment for recurrence[2,11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
