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Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone

1
Centre in Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4059, Australia
2
UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia
3
Department of Pediatric Surgery, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337 Munich, Germany
4
Australian Prostate Cancer Research Centre—Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4102, Australia
5
Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
6
Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Brettreichstraße 11, 97072 Wuerzburg, Germany
7
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 2800, Australia
8
Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia
9
ARC Industrial Transformation Training Centre In Additive Biomanufacturing, Queensland University of Technology (QUT), 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4059, Australia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2018, 10(11), 438; https://doi.org/10.3390/cancers10110438
Received: 28 September 2018 / Revised: 2 November 2018 / Accepted: 9 November 2018 / Published: 13 November 2018
(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)
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Abstract

The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγnull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies. View Full-Text
Keywords: prostate cancer; bone metastasis; tissue engineering; humanized bone; orthotopic model; cancer-associated fibroblasts; tumor microenvironment prostate cancer; bone metastasis; tissue engineering; humanized bone; orthotopic model; cancer-associated fibroblasts; tumor microenvironment
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McGovern, J.A.; Shafiee, A.; Wagner, F.; Lahr, C.A.; Landgraf, M.; Meinert, C.; Williams, E.D.; Russell, P.J.; Clements, J.A.; Loessner, D.; Holzapfel, B.M.; Risbridger, G.P.; Hutmacher, D.W. Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone. Cancers 2018, 10, 438.

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