摘要
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 tissueengineered 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-ΒLigand.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.
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 tissueengineered bone construct(hTEBC) was created within NOD-scid IL2 rgnull(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 h TEBC 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.
基金
supported by a grant from the Australian Government
