Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men worldwide. The introduction of prostate specific antigen (PSA) has greatly increased the number of men diagnosed with PCa but at the same time, as a result of the low specificity, led to overdiagnosis, resulting to unnecessary biopsies and high medical cost treatments.
The primary goal in PCa research today is to find a biomarker or biomarker set for clear and effecttive diagnosis of PCa as well as for distinction between aggressive and indolent cancers. Different proteomic technologies such as 2-D PAGE, 2-D DIGE, MALDI MS profiling, shotgun proteomics with label-based (ICAT, iTRAQ) and label-free (SWATH) quantification, MudPIT, CE-MS have been applied to the study of PCa in the past 15 years. Various biological samples, including tumor tissue, serum, plasma, urine, seminal plasma, prostatic secretions and prostatic-derived exosomes were analyzed with the aim of identifying diagnostic and prognostic biomarkers and developing a deeper understanding of the disease at the molecular level.
This review is focused on the overall analysis of expression proteomics studies in the PCa field investigating all types of human samples in the search for diagnostics biomarkers. Emphasis is given on proteomics platforms used in biomarker discovery and characterization, explored sources for PCa biomarkers, proposed candidate biomarkers by comparative proteomics studies and the possible future clinical application of those candidate biomarkers in PCa screening and diagnosis. In addition, we review the specificity of the putative markers and existing challenges in the proteomics research of PCa.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010; 127(12): 2893-2917.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1): 5-29.
3. Lilja H, Ulmert D, Vickers AJ. Prostate-specific antigen and prostate cancer: prediction, detection and monitoring. Nat Rev Cancer. 2008; 8(4): 268-278.
4. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. The New England journal of medicine. 1991; 324(17): 1156-1161.
5. Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. The New England journal of medicine. 1987; 317(15): 909-916.
6. Oberaigner W, Horninger W, Klocker H, Schonitzer D, Stuhlinger W, Bartsch G. Reduction of prostate cancer mortality in Tyrol, Austria, after introduction of prostate-specific antigen testing. Am J Epidemiol. 2006; 164(4): 376-384.
7. Potosky AL, Feuer EJ, Levin DL. Impact of screening on incidence and mortality of prostate cancer in the United States. Epidemiol Rev. 2001; 23(1): 181-186.
8. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012; 61(6): 1079-1092.
9. Nadler RB, Humphrey PA, Smith DS, Catalona WJ, Ratliff TL. Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate specific antigen levels. J Urol. 1995; 154(2 Pt 1): 407-413.
10. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate- specific antigen level < or = 4.0 ng per milliliter. The New England journal of medicine. 2004; 350(22): 2239-2246.
11. Thompson IM, Ankerst DP, Chi C, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005; 294(1): 66-70.
12. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst. 2009; 101(6): 374-383.
13. Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw. 2010; 8(2): 162-200.
14. Lapointe J, Li C, Higgins JP, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101(3): 811-816.
15. Sakr WA, Tefilli MV, Grignon DJ, et al. Gleason score 7 prostate cancer: a heterogeneous entity? Correlation with pathologic parameters and disease-free survival. Urology. 2000; 56(5): 730-734.
16. Hori S, Blanchet JS, McLoughlin J. From prostatespecific antigen (PSA) to precursor PSA (proPSA) isoforms: a review of the emerging role of proPSAs in the detection and management of early prostate cancer. BJU Int. 2013; 112(6): 717-728.
17. Vlaeminck-Guillem V, Ruffion A, Andre J, Devonec M, Paparel P. Urinary prostate cancer 3 test: toward the age of reason? Urology. 2010; 75(2): 447-453.
18. Sartori DA, Chan DW. Biomarkers in prostate cancer: what's new? Curr Opin Oncol. 2014; 26(3): 259-264.
19. Wolters T, van der Kwast TH, Vissers CJ, et al. False-negative prostate needle biopsies: frequency, histopathologic features, and follow-up. Am J Surg Pathol. 2010; 34(1): 35-43.
20. Goo YA, Goodlett DR. Advances in proteomic prostate cancer biomarker discovery. J Proteomics. 2010; 73(10): 1839-1850.
21. Pin E, Fredolini C, Petricoin EF, 3rd. The role of proteomics in prostate cancer research: biomarker discovery and validation. Clin Biochem. 2013; 46(6): 524-538.
22. Fredolini C, Liotta LA, Petricoin EF. Application of proteomic technologies for prostate cancer detection, prognosis, and tailored therapy. Crit Rev Clin Lab Sci. 2010; 47(3): 125-138.
23. Garbis SD, Townsend PA. Proteomics of human prostate cancer biospecimens: the global, systemswide perspective for protein markers with potential clinical utility. Expert Rev Proteomics. 2013; 10(4): 337-354.
24. Larkin SE, Zeidan B, Taylor MG, et al. Proteomics in prostate cancer biomarker discovery. Expert Rev Proteomics. 2010; 7(1): 93-102.
25. Flatley B, Malone P, Cramer R. MALDI mass spectrometry in prostate cancer biomarker discovery. Biochim Biophys Acta. 2014; 1844(5): 940-949.
26. Wright ME, Han DK, Aebersold R. Mass spectrometry- based expression profiling of clinical prostate cancer. Mol Cell Proteomics. 2005; 4(4): 545-554.
27. O'Farrell PH. High resolution two-dimensional electrophoresis of proteins. J Biol Chem. 1975; 250(10): 4007-4021.
28. Unlu M, Morgan ME, Minden JS. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis. 1997; 18(11): 2071-2077.
29. Lilley KS, Friedman DB. All about DIGE: quantification technology for differential-display 2D-gel proteomics. Expert Rev Proteomics. 2004; 1(4): 401-409.
30. Tonge R, Shaw J, Middleton B, et al. Validation and development of fluorescence two-dimensional differential gel electrophoresis proteomics technology. Proteomics. 2001; 1(3): 377-396.
31. Rabilloud T, Lelong C. Two-dimensional gel electrophoresis in proteomics: a tutorial. J Proteomics. 2011; 74(10): 1829-1841.
32. Oliveira BM, Coorssen JR, Martins-de-Souza D. 2DE: the phoenix of proteomics. J Proteomics. 2014; 104: 140-150.
33. Link AJ, Eng J, Schieltz DM, et al. Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol. 1999; 17(7): 676-682.
34. Patel VJ, Thalassinos K, Slade SE, et al. A comparison of labeling and label-free mass spectrometrybased proteomics approaches. J Proteome Res. 2009; 8(7): 3752-3759.
35. Stahl DC, Swiderek KM, Davis MT, Lee TD. Datacontrolled automation of liquid chromatography/tandem mass spectrometry analysis of peptide mixtures. J Am Soc Mass Spectrom. 1996; 7(6): 532-540.
36. Silva JC, Gorenstein MV, Li GZ, Vissers JP, Geromanos SJ. Absolute quantification of proteins by LCMSE: a virtue of parallel MS acquisition. Mol Cell Proteomics. 2006; 5(1): 144-156.
37. Liu Y, Chen J, Sethi A, et al. Glycoproteomic analysis of prostate cancer tissues by SWATH mass spectrometry discovers N-acylethanolamine acid amidase and protein tyrosine kinase 7 as signatures for tumor aggressiveness. Mol Cell Proteomics. 2014; 13(7): 1753-1768.
38. Liu Y, Huttenhain R, Collins B, Aebersold R. Mass spectrometric protein maps for biomarker discovery and clinical research. Expert Rev Mol Diagn. 2013; 13(8): 811-825.
39. Collins BC, Gillet LC, Rosenberger G, et al. Quantifying protein interaction dynamics by SWATH mass spectrometry: application to the 14-3-3 system. Nat Methods. 2013; 10(12): 1246-1253.
40. Liu Y, Huttenhain R, Surinova S, et al. Quantitative measurements of N-linked glycoproteins in human plasma by SWATH-MS. Proteomics. 2013; 13(8): 1247-1256.
41. Kim Y, Ignatchenko V, Yao CQ, et al. Identification of differentially expressed proteins in direct expressed prostatic secretions of men with organ-confined versus extracapsular prostate cancer. Mol Cell Proteomics. 2012; 11(12): 1870-1884.
42. Principe S, Kim Y, Fontana S, et al. Identification of prostate-enriched proteins by in-depth proteomic analyses of expressed prostatic secretions in urine. J Proteome Res. 2012; 11(4): 2386-2396.
43. Wolters DA, Washburn MP, Yates JR, 3rd. An automated multidimensional protein identification technology for shotgun proteomics. Anal Chem. 2001; 73(23): 5683-5690.
44. Domon B, Aebersold R. Mass spectrometry and protein analysis. Science. 2006; 312(5771): 212-217.
45. Pusch W, Kostrzewa M. Application of MALDITOF mass spectrometry in screening and diagnostic research. Curr Pharm Des. 2005; 11(20): 2577-2591.
46. Baggerly KA, Morris JS, Coombes KR. Reproducibility of SELDI-TOF protein patterns in serum: comparing datasets from different experiments. Bioinformatics. 2004; 20(5): 777-785.
47. Wright GL, Jr. SELDI proteinchip MS: a platform for biomarker discovery and cancer diagnosis. Expert Rev Mol Diagn. 2002; 2(6): 549-563.
48. McLerran D, Grizzle WE, Feng Z, et al. SELDI-TOF MS whole serum proteomic profiling with IMAC surface does not reliably detect prostate cancer. Clin Chem. 2008; 54(1): 53-60.
49. Kaiser T, Wittke S, Just I, et al. Capillary electrophoresis coupled to mass spectrometer for automated and robust polypeptide determination in body fluids for clinical use. Electrophoresis. 2004; 25(13): 2044-2055.
50. Kolch W, Neususs C, Pelzing M, Mischak H. Capillary electrophoresis-mass spectrometry as a powerful tool in clinical diagnosis and biomarker discovery. Mass Spectrom Rev. 2005; 24(6): 959-977.
52. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006; 6(5): 392-401.
53. Paweletz CP, Liotta LA, Petricoin EF, 3rd. New technologies for biomarker analysis of prostate cancer progression: Laser capture microdissection and tissue proteomics. Urology. 2001; 57(4 Suppl 1): 160-163.
54. Meehan KL, Holland JW, Dawkins HJ. Proteomic analysis of normal and malignant prostate tissue to identify novel proteins lost in cancer. Prostate. 2002; 50(1): 54-63.
55. Lin JF, Xu J, Tian HY, et al. Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis. Int J Cancer. 2007; 121(12): 2596-2605.
56. Ummanni R, Junker H, Zimmermann U, et al. Prohibitin identified by proteomic analysis of prostate biopsies distinguishes hyperplasia and cancer. Cancer Lett. 2008; 266(2): 171-185.
57. Ummanni R, Mundt F, Pospisil H, et al. Identification of clinically relevant protein targets in prostate cancer with 2D-DIGE coupled mass spectrometry and systems biology network platform. PloS one. 2011; 6(2): e16833.
58. Han ZD, Zhang YQ, He HC, et al. Identification of novel serological tumor markers for human prostate cancer using integrative transcriptome and proteome analysis. Med Oncol. 2012; 29(4): 2877-2888.
59. Alaiya AA, Al-Mohanna M, Aslam M, et al. Proteomics- based signature for human benign prostate hyperplasia and prostate adenocarcinoma. Int J Oncol. 2011; 38(4): 1047-1057.
60. Zheng Y, Xu Y, Ye B, et al. Prostate carcinoma tissue proteomics for biomarker discovery. Cancer. 2003; 98(12): 2576-2582.
61. Cheung PK, Woolcock B, Adomat H, et al. Protein profiling of microdissected prostate tissue links growth differentiation factor 15 to prostate carcinogenesis. Cancer Res. 2004; 64(17): 5929-5933.
62 . Liu AY, Zhang H, Sorensen CM, Diamond DL. Analysis of prostate cancer by proteomics using tissue specimens. J Urol. 2005; 173(1): 73-78.
63. Garbis SD, Tyritzis SI, Roumeliotis T, et al. Search for potential markers for prostate cancer diagnosis, prognosis and treatment in clinical tissue specimens using amine-specific isobaric tagging (iTRAQ) with two-dimensional liquid chromatography and tandem mass spectrometry. J Proteome Res. 2008; 7(8): 3146-3158.
64. Sun C, Song C, Ma Z, et al. Periostin identified as a potential biomarker of prostate cancer by iTRAQproteomics analysis of prostate biopsy. Proteome Sci. 2011; 9: 22.
65. Lexander H, Palmberg C, Hellman U, et al. Correlation of protein expression, Gleason score and DNA ploidy in prostate cancer. Proteomics. 2006; 6(15): 4370-4380.
66. Skvortsov S, Schafer G, Stasyk T, et al. Proteomics profiling of microdissected low- and high-grade prostate tumors identifies Lamin A as a discriminatory biomarker. J Proteome Res. 2011; 10(1): 259-268.
67. Khamis ZI, Iczkowski KA, Sahab ZJ, Sang QX. Protein profiling of isolated leukocytes, myofibroblasts, epithelial, Basal, and endothelial cells from normal, hyperplastic, cancerous, and inflammatory human prostate tissues. J Cancer. 2010; 1: 70-79.
68. Pang J, Liu WP, Liu XP, et al. Profiling protein markers associated with lymph node metastasis in prostate cancer by DIGE-based proteomics analysis. J Proteome Res. 2010; 9(1): 216-226.
69. Glen A, Gan CS, Hamdy FC, et al. iTRAQ-facilitated proteomic analysis of human prostate cancer cells identifies proteins associated with progression. J Proteome Res. 2008; 7(3): 897-907.
70. Petricoin EF, 3rd, Ornstein DK, Paweletz CP, et al. Serum proteomic patterns for detection of prostate cancer. J Natl Cancer Inst. 2002; 94(20): 1576-1578.
71. Ornstein DK, Rayford W, Fusaro VA, et al. Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml. J Urol. 2004; 172(4 Pt 1): 1302-1305.
72. Qu Y, Adam BL, Yasui Y, et al. Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients. Clin Chem. 2002; 48(10): 1835-1843.
73. Adam BL, Qu Y, Davis JW, et al. Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Res. 2002; 62(13): 3609-3614.
74. Malik G, Ward MD, Gupta SK, et al. Serum levels of an isoform of apolipoprotein A-II as a potential marker for prostate cancer. Clin Cancer Res. 2005; 11(3): 1073-1085.
75. Pan YZ, Xiao XY, Zhao D, et al. Application of surface- enhanced laser desorption/ionization time-offlight- based serum proteomic array technique for the early diagnosis of prostate cancer. Asian J Androl. 2006; 8(1): 45-51.
76. Kyselova Z, Mechref Y, Al Bataineh MM, et al. Alterations in the serum glycome due to metastatic prostate cancer. J Proteome Res. 2007; 6(5): 1822-1832.
77. Qin S, Ferdinand AS, Richie JP, O'Leary MP, Mok SC, Liu BC. Chromatofocusing fractionation and two-dimensional difference gel electrophoresis for low abundance serum proteins. Proteomics. 2005; 5(12): 3183-3192.
78. Jayapalan JJ, Ng KL, Razack AH, Hashim OH. Identification of potential complementary serum biomarkers to differentiate prostate cancer from benign prostatic hyperplasia using gel- and lectin-based proteomics analyses. Electrophoresis. 2012; 33(12): 1855-1862.
79. Bergamini S, Bellei E, Reggiani Bonetti L, et al. Inflammation: an important parameter in the search of prostate cancer biomarkers. Proteome Sci. 2014; 12: 32.
80. Byrne JC, Downes MR, O'Donoghue N, et al. 2DDIGE as a strategy to identify serum markers for the progression of prostate cancer. J Proteome Res. 2009; 8(2): 942-957.
81. Fan Y, Murphy TB, Byrne JC, Brennan L, Fitzpatrick JM, Watson RW. Applying random forests to identify biomarker panels in serum 2D-DIGE data for the detection and staging of prostate cancer. J Proteome Res. 2011; 10(3): 1361-1373.
82. Qingyi Z, Lin Y, Junhong W, et al. Unfavorable prognostic value of human PEDF decreased in highgrade prostatic intraepithelial neoplasia: a differential proteomics approach. Cancer Invest. 2009; 27(7): 794-801.
83. Le L, Chi K, Tyldesley S, et al. Identification of serum amyloid A as a biomarker to distinguish prostate cancer patients with bone lesions. Clin Chem. 2005; 51(4): 695-707.
84. Al-Ruwaili JA, Larkin SE, Zeidan BA, et al. Discovery of serum protein biomarkers for prostate cancer progression by proteomic analysis. Cancer Genomics Proteomics. 2010; 7(2): 93-103.
85. Rosenzweig CN, Zhang Z, Sun X, et al. Predicting prostate cancer biochemical recurrence using a panel of serum proteomic biomarkers. J Urol. 2009; 181(3): 1407-1414.
86. Lam YW, Mobley JA, Evans JE, Carmody JF, Ho SM. Mass profiling-directed isolation and identification of a stage-specific serologic protein biomarker of advanced prostate cancer. Proteomics. 2005; 5(11): 2927-2938.
87. Rehman I, Evans CA, Glen A, et al. iTRAQ identification of candidate serum biomarkers associated with metastatic progression of human prostate cancer. PloS one. 2012; 7(2): e30885.
88. Decramer S, Gonzalez de Peredo A, Breuil B, et al. Urine in clinical proteomics. Mol Cell Proteomics. 2008; 7(10): 1850-1862.
89. Rodriguez-Suarez E, Siwy J, Zurbig P, Mischak H. Urine as a source for clinical proteome analysis: from discovery to clinical application. Biochim Biophys Acta. 2014; 1844(5): 884-898.
90. Theodorescu D, Fliser D, Wittke S, et al. Pilot study of capillary electrophoresis coupled to mass spectrometry as a tool to define potential prostate cancer biomarkers in urine. Electrophoresis. 2005; 26(14): 2797-2808.
91. Theodorescu D, Schiffer E, Bauer HW, et al. Discovery and validation of urinary biomarkers for prostate cancer. Proteomics Clin Appl. 2008; 2(4): 556-570.
92. Schiffer E, Bick C, Grizelj B, Pietzker S, Schofer W. Urinary proteome analysis for prostate cancer diagnosis: cost-effective application in routine clinical practice in Germany. Int J Urol. 2012; 19(2): 118-125.
93. M'Koma AE, Blum DL, Norris JL, et al. Detection of pre-neoplastic and neoplastic prostate disease by MALDI profiling of urine. Biochem Biophys Res Commun. 2007; 353(3): 829-834.
94. True LD, Zhang H, Ye M, et al. CD90/THY1 is overexpressed in prostate cancer-associated fibroblasts and could serve as a cancer biomarker. Mod Pathol. 2010; 23(10): 1346-1356.
95. Haj-Ahmad TA, Abdalla MA, Haj-Ahmad Y. Potential Urinary Protein Biomarker Candidates for the Accurate Detection of Prostate Cancer among Benign Prostatic Hyperplasia Patients. J Cancer. 2014; 5(2): 103-114.
96. Kiprijanovska S, Stavridis S, Stankov O, et al. Mapping and Identification of the Urine Proteome of Prostate Cancer Patients by 2D PAGE/MS. Int J Proteomics. 2014; 2014: 594761.
97. Davalieva K, Kiprijanovska S, Komina S, Petrusevska G, Zografska NC, Polenakovic M. Proteomics analysis of urine reveals acute phase response proteins as candidate diagnostic biomarkers for prostate cancer. Proteome Sci. 2015; 13(1): 2.
98. Jayapalan JJ, Ng KL, Shuib AS, Razack AH, Hashim OH. Urine of patients with early prostate cancer contains lower levels of light chain fragments of interalpha- trypsin inhibitor and saposin B but increased expression of an inter-alpha-trypsin inhibitor heavy chain 4 fragment. Electrophoresis. 2013; 34(11): 1663-1669.
99. Rehman I, Azzouzi AR, Catto JW, et al. Proteomic analysis of voided urine after prostatic massage from patients with prostate cancer: a pilot study. Urology. 2004; 64(6): 1238-1243.
100. Okamoto A, Yamamoto H, Imai A, et al. Protein profiling of post-prostatic massage urine specimens by surface-enhanced laser desorption/ionization timeof- flight mass spectrometry to discriminate between prostate cancer and benign lesions. Oncol Rep. 2009; 21(1): 73-79.
101. Nakayama K, Inoue T, Sekiya S, et al. The C-terminal fragment of prostate-specific antigen, a 2331 Da peptide, as a new urinary pathognomonic biomarker candidate for diagnosing prostate cancer. PloS one. 2014; 9(9): e107234.
102. Flatley B, Wilmott KG, Malone P, Cramer R. MALDI MS profiling of post-DRE urine samples highlights the potential of beta-microseminoprotein as a marker for prostatic diseases. Prostate. 2014; 74(1): 103-111.
103. Bijnsdorp IV, Geldof AA, Lavaei M, Piersma SR, van Moorselaar RJ, Jimenez CR. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J Extracell Vesicles. 2013; 2.
104. Hassan MI, Kumar V, Kashav T, Alam N, Singh TP, Yadav S. Proteomic approach for purification of seminal plasma proteins involved in tumor proliferation. J Sep Sci. 2007; 30(12): 1979-1988.
105. Neuhaus J, Schiffer E, von Wilcke P, et al. Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease. PloS one. 2013; 8(6): e67514.
106. Hanash SM, Pitteri SJ, Faca VM. Mining the plasma proteome for cancer biomarkers. Nature. 2008; 452(7187): 571-579.
107. Anderson NL, Anderson NG. The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics. 2002; 1(11): 845-867.