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

被引：0

作者：

Nathalie Bock ^{[1
,2
,3
]}

Ali Shokoohmand ^{[1
,2
,3
]}

Thomas Kryza ^{[1
,2
]}

Joan R?hl ^{[1
,2
]}

Jonelle Meijer ^{[1
,2
,3
]}

Phong A.Tran ^{[3
,4
]}

Colleen C.Nelson ^{[1
,2
]}

Judith A.Clements ^{[1
,2
]}

Dietmar W.Hutmacher ^{[1
,2
,3
,4
,5
]}

机构：

[1] 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)

[2] Australian Research Council(ARC) Training Centre in Additive Biomanufacturing,QUT

[3] Centre in Regenerative Medicine,QUT

[4] Bone and Joint Disorders Program,School of Chemistry,Physics and Mechanical Engineering,Science and Engineering Faculty(SEF),QUT

[5] Translational Research Institute(TRI)

来源：

Bone Research | 2019年 / 02期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

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

D O I：

暂无

中图分类号：

R737.25 [前列腺肿瘤];

学科分类号：

100214 ;

摘要：

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 understood.Here,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 microenvironment.The model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds,leading to a mineralized osteoblast-derived microtissue containing,in a 3 D setting,viable osteoblastic cells,osteocytic cells,and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins,and mineral content.Direct co-culture of androgen receptordependent/independent cell lines(LNCaP,C4-2 B,and PC3) led cancer cells to display functional and molecular features as observed in vivo.Co-cultured cancer cells showed increased affinity to the microtissues,as a function of their bone metastatic potential.Cocultures led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation,consistent with the clinical marker profile of osteoblastic bone metastases.LNCaP 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 resistance.The 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.

引用

页码：157 / 170

页数：14