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Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment

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Bone Research 2019年第2期7卷 157-170页

作者： Nathalie Bock Ali Shokoohmand Thomas Kryza Joan Rohl jonelle meijer Phong A. Tran Colleen C. Nelson Judith A. Clements Dietmar W. Hutmacher School of Biomedical Sciences Faculty of Health and Australian Prostate Cancer Research Centre (APCRC-Q)Institute of Health and Biomedical Innovation (IHBI)Queensland University of Technology (QUT)BrisbaneQLD 4000Australia Translational Research Institute (TRI) WoolloongabbaQLD 4102Australia Centre in Regenerative Medicine QUTKelvin GroveQLD 4059Australia Bone and Joint Disorders Program School of ChemistryPhysics and Mechanical EngineeringScience and Engineering Faculty (SEF)QUTBrisbaneQLD 4000Australia Australian Research Council (ARC) Training Centre in Additive Biomanufacturing QUTKelvin GroveQLD 4059Australia

While stromal interactions are essential in cancer adaptation to hormonal therapies,the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly ***,we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases,and used it to study the effects of androgen deprivation in this *** model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds,leading to a mineralized osteoblast-derived microtissue containing,in a 3D setting,viable osteoblastic cells,osteocytic cells,and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins,and mineral *** co-culture of androgen receptordependent/ independent cell lines (LNCaP,C4-2B,and PC3) led cancer cells to display functional and molecular features as observed in ***-cultured cancer cells showed increased affinity to the microtissues,as a function of their bone metastatic *** led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation,consistent with the clinical marker profile of osteoblastic bone *** showed a significant adaptive response under androgen deprivation in the microtissues,with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase,enolase 2).Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor,alkaline phosphatase,and dopa decarboxylase,as seen in the transition towards *** unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.

关键词： Engineering osteoblastic metastases the adaptive response metastatic microenvironment

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