title: iTRAQ identification of candidate serum biomarkers associated with metastatic progression of human prostate cancer.
abstract: A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n = 5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer 'BPH', (ii) localised cancer with no evidence of progression, 'non-progressing' (iii) localised cancer with evidence of biochemical progression, 'progressing', and (iv) bone metastasis at presentation 'metastatic'. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (p<0.001). Comparisons of metastatic versus progressing groups identified the significant differential expression of 23 proteins. Mapping the differentially expressed proteins onto the prostate cancer progression pathway revealed the dysregulated expression of individual proteins, pairs of proteins and 'panels' of proteins to be associated with particular stages of disease development and progression. The median immunostaining intensity of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p = 0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation.
authors.affiliation: Department of Human Metabolism, The Medical School, The Mellanby Centre for Bone Research, University of Sheffield, Sheffield, United Kingdom. i.rehman@sheffield.ac.uk
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Rehman
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Evans
authors.forename: Adam
authors.initials: A
authors.lastname: Glen
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Colby L
authors.initials: CL
authors.lastname: Eaton
authors.forename: Jenny
authors.initials: J
authors.lastname: Down
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pesce
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Phillips
authors.forename: Ow Saw
authors.initials: OS
authors.lastname: Yen
authors.forename: George N
authors.initials: GN
authors.lastname: Thalmann
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Wright
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D018450:Disease Progression; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D060787:Neoplasm Grading; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C094814:EEF1A1 protein, human; C503234:EEF1A2 protein, human; D020648:Peptide Elongation Factor 1; D012333:RNA, Messenger; D017430:Prostate-Specific Antigen