title: Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel.
abstract: Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Pedram
authors.initials: P
authors.lastname: Kharaziha
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Chioureas
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Science for Life Laboratory, Stockholm, Sweden.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Rutishauser
authors.affiliation: Department of Medicine, School of Health Sciences, University of Athens, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Baltatzis
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Lennartsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Pedro
authors.initials: P
authors.lastname: Fonseca
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Alireza
authors.initials: A
authors.lastname: Azimi
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet and University Hospital, Huddinge, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Hultenby
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Science for Life Laboratory, Stockholm, Sweden.
authors.forename: Roman
authors.initials: R
authors.lastname: Zubarev
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Ullén
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yachnin
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Nilsson
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Theocharis
authors.initials: T
authors.lastname: Panaretakis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor / Q000187:drug effects; D015331:Cohort Studies; D019295:Computational Biology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000187:drug effects* / Q000378:metabolism; D005109:Extracellular Matrix; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000737:chemistry; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D020543:Proteome; D043823:Taxoids / Q000737:chemistry* / Q000627:therapeutic use*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001798:Blood Proteins; D047908:Intracellular Signaling Peptides and Proteins; C104581:PABPC4 protein, human; D039102:Poly(A)-Binding Proteins; D020543:Proteome; C105159:SH3GL1 protein, human; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel; C095122:multidrug resistance protein 3
keywords: biomarkers; docetaxel; exosomes; prostate cancer; resistance
references.citation: Cell. 1996 Nov 1;87(3):507-17
references.pmid: 8898203
references.citation: Blood. 1999 Dec 1;94(11):3791-9
references.pmid: 10572093
references.citation: PLoS One. 2012;7(8):e40716
references.pmid: 22870202
references.citation: Eur Urol. 2011 May;59(5):823-31
references.pmid: 21196075
references.citation: N Engl J Med. 2004 Oct 7;351(15):1502-12
references.pmid: 15470213
references.citation: J Clin Oncol. 2010 Mar 20;28(9):1489-95
references.pmid: 20159823
references.citation: J Clin Oncol. 2008 Jan 10;26(2):242-5
references.pmid: 18182665
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Nat Rev Cancer. 2010 Mar;10(3):194-204
references.pmid: 20147901
references.citation: Curr Protoc Cell Biol. 2006 Apr;Chapter 3:Unit 3.22
references.pmid: 18228490
references.citation: PLoS One. 2013;8(7):e70047
references.pmid: 23936141
references.citation: J Cell Physiol. 2012 Feb;227(2):658-67
references.pmid: 21465472
references.citation: PLoS One. 2013;8(12):e82589
references.pmid: 24391718
references.citation: Nat Rev Cancer. 2008 Apr;8(4):268-78
references.pmid: 18337732
references.citation: Anal Biochem. 2012 Sep 1;428(1):44-53
references.pmid: 22691960
references.citation: Cold Spring Harb Symp Quant Biol. 2006;71:537-43
references.pmid: 17381337
references.citation: Cell Biochem Biophys. 2011 Jul;60(3):137-54
references.pmid: 21184288
references.citation: Biochim Biophys Acta. 2013 Jul;1831(7):1302-9
references.pmid: 24046871
references.citation: J Clin Oncol. 2009 Aug 10;27(23):3742-8
references.pmid: 19470933
references.citation: J Cell Physiol. 2013 Jul;228(7):1487-95
references.pmid: 23254476
references.citation: Cancer Res. 1999 Nov 15;59(22):5719-23
references.pmid: 10582690
references.citation: J Extracell Vesicles. 2012 Apr 16;1:null
references.pmid: 24009879
references.citation: Gynecol Oncol. 2008 Jul;110(1):13-21
references.pmid: 18589210
references.citation: J Clin Invest. 2008 Sep;118(9):3051-64
references.pmid: 18725989
references.citation: Mol Cell Proteomics. 2013 Aug;12(8):2324-31
references.pmid: 23589346
references.citation: Expert Rev Proteomics. 2014 Apr;11(2):167-77
references.pmid: 24564711
references.citation: PLoS One. 2012;7(12):e50999
references.pmid: 23251413
references.citation: Nat Cell Biol. 2003 Feb;5(2):97-9
references.pmid: 12563272
references.citation: Nat Rev Clin Oncol. 2011 Jan;8(1):12-23
references.pmid: 20859283
references.citation: Methods Mol Biol. 2009;522:211-9
references.pmid: 19247615
references.citation: J Mol Med (Berl). 2013 Apr;91(4):431-7
references.pmid: 23519402
references.citation: J Urol. 2014 Apr;191(4):1132-8
references.pmid: 24211598
references.citation: Prostate Cancer Prostatic Dis. 2010 Mar;13(1):6-11
references.pmid: 19581923
references.citation: Sci Transl Med. 2012 Mar 28;4(127):127rv3
references.pmid: 22461644
references.citation: J Clin Oncol. 2010 Mar 20;28(9):1481-8
references.pmid: 20159824
references.citation: J Cell Biochem. 2010 Oct 1;111(2):488-96
references.pmid: 20533300
references.citation: Biochim Biophys Acta. 2012 Nov-Dec;1819(11-12):1154-63
references.pmid: 22982408
references.citation: Mol Cancer. 2014;13:145
references.pmid: 24913355
references.citation: J Cell Biol. 2012 Feb 6;196(3):375-85
references.pmid: 22291036