title: Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts.
abstract: We previously established a role for cancer-associated fibroblasts (CAF) in enhancing the self-renewal and differentiation potentials of putative prostate cancer stem cells (CSC). Our published work focused on androgen-dependent prostate cancer (ADPC) using the conditional Pten deletion mouse model. Employing the same model, we now describe the interaction of CAF and CSC in castration-resistant prostate cancer (CRPC). CAF isolated from ADPC (ADPCAF) and from CRPC (CRPCAF) were compared in terms of their ability to support organoid formation and tumor initiation by CSC from CRPC (CRPCSC) in vitro and in vivo. CRPCSC formed spheroids in vitro and well-differentiated glandular structures under the renal capsules of recipient mice in vivo more effectively in the presence of CRPCAF compared to ADPCAF. Furthermore, whereas CSC with CAF from ADPC formed mostly well-differentiated tumors in our previous study, we now show that CRPCSC, when combined with CRPCAF (but not ADPCAF), can form aggressive, poorly-differentiated tumors. The potential of CRPCAF to support organoid/tumor formation by CRPCSC remained greater even when compared to 10-fold more ADPCAF, suggesting that paracrine factors produced specifically by CRPCAF preferentially potentiate the stemness and tumorigenic properties of the corresponding CSC. This apparently unique property of CRPCAF was notable when the CAF and CSC were grafted in either intact or castrated recipient mice. In both environments, CRPCAF induced in the epithelial compartment higher proliferative activity compared to ADPCAF, indicated by a higher Ki67 index. Factors released by CRPCAF to regulate CRPCSC may be targeted to develop novel therapeutic approaches to manage advanced prostate cancer.
authors.affiliation: Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California; Institute for Genetic Medicine, University of Southern California, Los Angeles, California.
authors.forename: Helty
authors.initials: H
authors.lastname: Adisetiyo
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liang
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liao
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Jeong
authors.forename: Michael B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Pradip
authors.initials: P
authors.lastname: Roy-Burman
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002369:Castration; D002454:Cell Differentiation; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019899:Paracrine Communication; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D018874:Spheroids, Cellular; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
references.citation: Cancer Biol Ther. 2005 Jan;4(1):4-5
references.pmid: 16052746
references.citation: Stem Cells. 2007 Nov;25(11):2760-9
references.pmid: 17641240
references.citation: BJU Int. 2012 Feb;109 Suppl 1:22-9
references.pmid: 22239226
references.citation: Cancer Cell. 2007 Jan;11(1):3-5
references.pmid: 17222787
references.citation: Cancer Res. 2005 Oct 1;65(19):8887-95
references.pmid: 16204060
references.citation: Mol Cell Endocrinol. 2012 Sep 5;360(1-2):14-24
references.pmid: 21802490
references.citation: Cancer Res. 2007 Aug 1;67(15):7525-33
references.pmid: 17671224
references.citation: Histol Histopathol. 2007 Sep;22(9):1043-9
references.pmid: 17523082
references.citation: Cancer Res. 2010 Sep 15;70(18):7294-303
references.pmid: 20807814
references.citation: J Clin Oncol. 2011 Sep 20;29(27):3651-8
references.pmid: 21859989
references.citation: Cancer Res. 2006 Aug 15;66(16):7889-98
references.pmid: 16912162
references.citation: Endocr Relat Cancer. 2010 Sep 23;17(4):R273-85
references.pmid: 20660571
references.citation: Eur J Cancer. 2006 Jun;42(9):1213-8
references.pmid: 16632344
references.citation: Cancer Res. 2008 Jan 1;68(1):198-205
references.pmid: 18172312
references.citation: PLoS One. 2013 Jul 31;8(7):e69484
references.pmid: 23936028
references.citation: Clin Cancer Res. 2006 Mar 15;12(6):1665-71
references.pmid: 16551847
references.citation: Cancer Cell. 2007 Jan;11(1):69-82
references.pmid: 17222791
references.citation: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6942-7
references.pmid: 15860580
references.citation: Nat Rev Urol. 2013 Aug;10(8):441-51
references.pmid: 23857181
references.citation: Biomaterials. 2013 Jul;34(20):4777-85
references.pmid: 23562048
references.citation: Prostate Cancer Prostatic Dis. 2008;11(1):32-9
references.pmid: 17984999
references.citation: Cancer Biol Ther. 2006 Aug;5(8):901-6
references.pmid: 16855379
references.citation: J Natl Cancer Inst. 2011 Nov 16;103(22):1665-75
references.pmid: 21917607
references.citation: Cancer Cell. 2003 Sep;4(3):209-21
references.pmid: 14522255
references.citation: Cancer Res. 2007 Jun 15;67(12):5683-90
references.pmid: 17553900
references.citation: Cell Growth Differ. 2001 Dec;12(12):631-40
references.pmid: 11751458