title: Species-specific homing mechanisms of human prostate cancer metastasis in tissue engineered bone.
abstract: The development of effective therapeutic strategies against prostate cancer bone metastases has been impeded by the lack of adequate animal models that are able to recapitulate the biology of the disease in humans. Bioengineered approaches allow researchers to create sophisticated experimentally and physiologically relevant in vivo models to study interactions between cancer cells and their microenvironment under reproducible conditions. The aim of this study was to engineer a morphologically and functionally intact humanized organ bone which can serve as a homing site for human prostate cancer cells. Transplantation of biodegradable tubular composite scaffolds seeded with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone construct including a large number of human mesenchymal cells which were shown to be metabolically active and capable of producing extracellular matrix components. Micro-CT analysis demonstrated that the newly formed ossicle recapitulated the morphological features of a physiological organ bone with a trabecular network surrounded by a cortex-like outer structure. This microenvironment was supportive of the lodgement and maintenance of murine haematopoietic cell clusters, thus mimicking a functional organ bone. Bioluminescence imaging demonstrated that luciferase-transduced human PC3 cells reproducibly homed to the humanized tissue engineered bone constructs, proliferated, and developed macro-metastases. This model allows the analysis of interactions between human prostate cancer cells and a functional humanized bone organ within an immuno-incompetent murine host. The system can serve as a reproducible platform to study effects of therapeutics against prostate cancer bone metastases within a humanized microenvironment.
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia; Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97072 Wuerzburg, Germany. Electronic address: holzapfel@orthopaedic-oncology.net.
authors.forename: Boris M
authors.initials: BM
authors.lastname: Holzapfel
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia; Department of Orthopedics, University of Regensburg, Asklepios Klinikum Bad Abbach, Kaiser-Karl V.-Allee 3, 93077 Bad Abbach, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Wagner
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Loessner
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Nina P
authors.initials: NP
authors.lastname: Holzapfel
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Laure
authors.initials: L
authors.lastname: Thibaudeau
authors.affiliation: Orthopedic Surgery, Prince Charles Hospital, Rode Road, Chermside, Brisbane, QLD 4032, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Crawford
authors.affiliation: Australian Prostate Cancer Research Centre, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia; Cells and Tissue Domain, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
authors.affiliation: Australian Prostate Cancer Research Centre, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia; Cells and Tissue Domain, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Clements
authors.affiliation: Australian Prostate Cancer Research Centre, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia; Cells and Tissue Domain, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.affiliation: Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4049, Australia; George W Woodruff School of Mechanical Engineering, Georgia Institute of Technology, 801 Ferst Drive Northwest, Atlanta, GA 30332, USA; Institute for Advanced Study, Technical University Munich, Lichtenbergstr. 2a, 85748 Garching, Munich, Germany. Electronic address: dietmar.hutmacher@qut.edu.au.
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Hutmacher
mesh_terms: D001859:Bone Neoplasms / Q000556:secondary*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011471:Prostatic Neoplasms / Q000150:complications*; D023822:Tissue Engineering; D055114:X-Ray Microtomography
keywords: Bone metastasis; Homing; Humanized bone; Osteotropism; Prostate cancer; Tissue engineering