Humanized bone facilitates prostate cancer metastasis and recapitulates therapeutic effects of zoledronic acid in vivo

Marietta Landgraf,Christoph A Lahr,Christoph Meinert,Ali Shokoohmand,Jacqui A Mcgovern,Pamela M Pollock,Abbas Shafiee,Dietmar W Hutmacher,Alvaro Sanchez-Herrero

doi:10.1038/s41413-019-0072-9

Abstract

Advanced prostate cancer (PCa) is known for its high prevalence to metastasize to bone, at which point it is considered incurable. Despite significant effort, there is no animal model capable of recapitulating the complexity of PCa bone metastasis. The humanized mouse model for PCa bone metastasis used in this study aims to provide a platform for the assessment of new drugs by recapitulating the human–human cell interactions relevant for disease development and progression. The humanized tissue-engineered bone construct (hTEBC) was created within NOD-scid IL2rgnull (NSG) mice and was used for the study of experimental PC3-Luc bone metastases. It was confirmed that PC3-Luc cells preferentially grew in the hTEBC compared with murine bone. The translational potential of the humanized mouse model for PCa bone metastasis was evaluated with two clinically approved osteoprotective therapies, the non-species-specific bisphosphonate zoledronic acid (ZA) or the human-specific antibody Denosumab, both targeting Receptor Activator of Nuclear Factor Kappa-Β Ligand. ZA, but not Denosumab, significantly decreased metastases in hTEBCs, but not murine femora. These results highlight the importance of humanized models for the preclinical research on PCa bone metastasis and indicate the potential of the bioengineered mouse model to closely mimic the metastatic cascade of PCa cells to human bone. Eventually, it will enable the development of new effective antimetastatic treatments.

Highlights

Prostate cancer (PCa) is the second most frequently diagnosed cancer among the male population in industrialized countries.[1]
The humanized tissueengineered bone construct (hTEBC) consisted of a in more depth, ex vivo Bioluminescence imaging (BLI) was performed after explantation tubular medical-grade polycaprolactone scaffold seeded with human osteoblasts and a pre-vascularized gelatin methacryloyl (GelMA)-core containing human umbilical vein endothelial cells (HUVECs) and multipotent mesenchymal stromal cells (MSCs) (Fig. 1a)
The hTEBCs of animals treated with zoledronic acid (ZA) had a mean total flux of 1.27 × 104 ± 4.99 × 103 p·s−1, which was significantly lower than both Denosumab (4.04 × 105 ± 2.19 × 105 p·s−1; mean ± SEM; n = 11; P = 0.000 5) and PBS (6.38 × 104 ± 2.24 × 104 p·s−1, mean ± SEM, n = 10, P = 0.01)

Summary

Introduction

Prostate cancer (PCa) is the second most frequently diagnosed cancer among the male population in industrialized countries.[1] Approximately 50% of patients suffering from advanced PCa experience at least one complication within 2 years due to the development of bone metastases.[2] These so-called skeletal-related events (SREs) are associated with poor prognosis, severe bone pain, pathological fractures, and imply in most cases the incurability of the disease.[3,4] it is rather the health implications of bone metastases developing in later disease stages than the primary tumor itself that accounts for the mostly lethal outcome of PCa.[3,5] The current gold standard of therapy for patients with PCa metastases is a combination of Taxane and corticosteroids, e.g., Docetaxel and Prednisone.[6] The 5-

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Conclusion