Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment.
Bone cancer
Journal
Bone research
ISSN: 2095-4700
Titre abrégé: Bone Res
Pays: China
ID NLM: 101608652
Informations de publication
Date de publication:
2019
2019
Historique:
received:
23
10
2018
revised:
13
02
2019
accepted:
04
03
2019
entrez:
3
5
2019
pubmed:
3
5
2019
medline:
3
5
2019
Statut:
epublish
Résumé
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 3D setting, viable osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins, and mineral content. Direct co-culture of androgen receptor-dependent/independent cell lines (LNCaP, C4-2B, 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. Co-cultures 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.
Identifiants
pubmed: 31044095
doi: 10.1038/s41413-019-0049-8
pii: 49
pmc: PMC6486620
doi:
Types de publication
Journal Article
Langues
eng
Pagination
13Déclaration de conflit d'intérêts
The authors declare no competing interests.
Références
J Bone Miner Res. 2009 Nov;24(11):1927-35
pubmed: 19419324
Endocr Rev. 2013 Oct;34(5):658-90
pubmed: 23612223
Biomaterials. 2013 Jul;34(22):5538-51
pubmed: 23623428
Dev Dyn. 2006 Jan;235(1):176-90
pubmed: 16258960
Osteoporos Int. 2014 Feb;25(2):645-51
pubmed: 23903956
Clin Exp Metastasis. 2004;21(5):399-408
pubmed: 15672864
Clin Chem. 1995 Oct;41(10):1489-94
pubmed: 7586522
Nat Protoc. 2017 Apr;12(4):639-663
pubmed: 28253234
PLoS One. 2015 Nov 06;10(11):e0142058
pubmed: 26545120
Urology. 2002 Feb;59(2):277-80
pubmed: 11834402
Front Oncol. 2014 Dec 23;4:370
pubmed: 25566507
Br J Cancer. 2017 Jan 17;116(2):227-236
pubmed: 28006818
Drugs Today (Barc). 2002 Feb;38(2):91-102
pubmed: 12532187
Expert Opin Investig Drugs. 2013 Nov;22(11):1385-400
pubmed: 24024652
Clin Exp Metastasis. 2014 Mar;31(3):269-83
pubmed: 24292404
Clin Chem. 2011 Oct;57(10):1366-75
pubmed: 21956922
Trends Biotechnol. 2018 Mar;36(3):242-251
pubmed: 29310843
Cancer Res. 2010 May 1;70(9):3780-90
pubmed: 20388789
Cancer Lett. 2015 Oct 10;367(1):12-7
pubmed: 26185001
Biomaterials. 2016 Nov;108:197-213
pubmed: 27639438
Calcif Tissue Int. 2014 Jan;94(1):25-34
pubmed: 24002178
Nat Rev Urol. 2015 Jun;12(6):340-56
pubmed: 26119830
BJU Int. 2015 Apr;115 Suppl 5:3-13
pubmed: 25327530
Nat Genet. 1995 Apr;9(4):401-6
pubmed: 7795646
Biofabrication. 2013 Jun;5(2):025001
pubmed: 23443534
Bonekey Rep. 2015 Jun 24;4:716
pubmed: 26131363
J Cell Mol Med. 2009 Aug;13(8A):1417-27
pubmed: 19627398
Cancer Res. 2006 Jan 15;66(2):883-8
pubmed: 16424021
Bonekey Rep. 2014 Jun 04;3:543
pubmed: 24991406
Nat Rev Cancer. 2005 Jan;5(1):21-8
pubmed: 15630412
Clin Cancer Res. 2014 Jun 1;20(11):2846-50
pubmed: 24727321
Mol Cancer. 2007 Jun 06;6:38
pubmed: 17553164
PLoS One. 2011;6(10):e25900
pubmed: 21991382
Bone. 2016 Jul;88:146-156
pubmed: 27150828
Microarrays (Basel). 2015 Oct 29;4(4):503-19
pubmed: 27600237
Clin Cancer Res. 2004 Mar 1;10(5):1860-9
pubmed: 15014041
Bone Res. 2018 Feb 26;6:3
pubmed: 29507817
Curr Mol Med. 2013 May;13(4):626-39
pubmed: 23061677
Clin Chem. 2013 Jan;59(1):75-84
pubmed: 23204221
Oncotarget. 2016 Jul 12;7(28):44803-44820
pubmed: 27027241
Biomaterials. 2013 Jul;34(20):4777-85
pubmed: 23562048
Future Oncol. 2012 Jul;8(7):803-17
pubmed: 22830401
Bone Res. 2018 May 24;6:16
pubmed: 29844945
Bone Res. 2018 Feb 26;6:5
pubmed: 29507819
Nat Protoc. 2009;4(11):1591-613
pubmed: 19834475
J Cell Biochem. 2004 Mar 1;91(4):718-29
pubmed: 14991763
Nat Mater. 2010 Feb;9(2):90-3
pubmed: 20094076
Anticancer Res. 2016 Mar;36(3):1193-201
pubmed: 26977015
Cancer Microenviron. 2011 Dec;4(3):221-35
pubmed: 21826451
Cytokine Growth Factor Rev. 2005 Jun;16(3):319-27
pubmed: 15869900
Br J Cancer. 2016 Mar 15;114(6):659-68
pubmed: 26954717
Endocrinology. 2015 Dec;156(12):4534-44
pubmed: 26393301
Nat Methods. 2012 Jul;9(7):671-5
pubmed: 22930834
Nat Rev Clin Oncol. 2014 Jun;11(6):335-45
pubmed: 24821212