The Present and Future of Prostate Cancer Urine Biomarkers
Abstract
:1. Introduction
2. Urine: A Source of Prostate Cancer Biomarkers
2.1. DNA-Based Urinary Biomarkers
2.2. RNA-Based Urine Biomarkers
2.3. miRNA-Based Urine Biomarkers
2.4. Protein-Based Urine Biomarkers
2.5. Metabolite-Based Urine Biomarkers
2.6. Urine Biomarker Panels
2.7. Exosomes as a Source of Urine Biomarkers
3. Conclusions
Acknowledgments
Conflict of Interest
References
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Gene | Description | Gene type | Expression | Type of biomarker | Sample | References |
---|---|---|---|---|---|---|
AMACR (P504) | Alpha-Methylacyl-CoA Racemase | Enzyme involved in branched chain fatty acid oxidation | Over-expressed in PCa (also in HGPIN) and in some other carcinomas, both at RNA and protein level | Diagnostic (in gray zone) and prognostic | Tissue, blood and urine | [20,21] |
ANXA3 | Annexin A3 | Calcium and phospholipid binding protein | Presence in urinary exosomes and proteasomes. Lower production in PCa than in BPH, HGPIN and benign | Prognostic (able to stratify a large group of intermediate-risk patients into high- and low-risk subgroups) | Tissue and urine | [22–24] |
APC | Adenomatous polyposis coli | Tumor suppressor. Promotes rapid degradation of CTNNB1 and participates in Wnt signaling as a negative regulator. | APC methylation higher in PCa than in BPH. Methylation level correlates positively with Gleason score | Diagnostic and prognostic | Tissue and Urine DNA | [25] |
AR | Androgen receptor | Receptor for androgen stimulation of prostate. | Over-expression associated with poor prognosis prostate cancer and metastasis | Prognostic | Tissue RNA and IHC | [26–28] |
AURKA | Aurora kinase. | Aurora kinase. AURKA is a centrosome-associated serine/threonine kinase involved in mitotic chromosomal segregation. | Amplified and over-expressed in certain types of poor prognosis prostate cancer | Prognostic | Tissue RNA and DNA | [29–31] |
AZGP1 | Alpha-2-glycoprotein 1, zinc binding. Alias. ZAG | Stimulates lipid degradation in adipocytes and causes the extensive fat losses associated with some advanced cancers. May bind polyunsaturated fatty acids. | Over-expressed in PCa. Low AZGP1 expression predicts for recurrence in margin-positive, localized PCa | Diagnostic, prognostic | Tissue, blood and urine | [32–34] |
BRAF | v-raf murine sarcoma viral oncogene homolog B1 | Belongs to the raf/mil family of serine/threonine protein kinases and is involved in the regulation of the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation. | SLC45A3-BRAF fusion gene, mutations and gain in prostate cancer | Diagnostic and therapeutic target | Tissue RNA and DNA | [35–37] |
CAMKK2 | Calcium/calmodulindependent protein kinase kinase 2. | AR target gene promoting biosynthesis and glycolysis | Down-regulation of calcium/calmodulin-dependent protein kinase kinase 2 by androgen deprivation induces castration-resistant prostate cancer. | Prognostic | Tissue RNA | [38–40] |
CDH1 | Cadherin 1, type 1, E-cadherin (epithelial) | Epithelial cell - cell adhesion molecule | Reduced production in 50% of tumors. E-cadherin production by epithelial cells has been shown to predict PCa prognosis | Prognostic (correlated with grade, tumor stage, and survival) | Tissue | [41,42] |
CLU | Clusterin | Function unknown, but is thought to be involved in several basic biological events such as cell death and tumor progression. | Developed as a potential therapeutic target | Therapeutic target | Tissue, exosome protein | [43–46] |
CRISP-3 | Cysteine-Rich Secretory Protein 3 | Secreted protein produced in the male reproductive tract, is involved in sperm maturation | Large amounts have been detected in seminal plasma. Over-expressed in HGPIN and PCa. | Prognostic | Tissue | [47,48] |
EPCA | Early Prostate Cancer Antigen | Nuclear matrix protein | Over-expressed in PCa | Diagnostic (for predicting repeated BP) | Tissue and blood | [49,50] |
EPCA-2 | Early Prostate Cancer Antigen 2 | Nuclear matrix protein | Over-expressed in PCa | Diagnostic and Prognostic (differentiate localized PCa from metastatic PCa) | Blood | [51] |
FOLH1/PS MA | Folate hydrolase 1/Prostate Specific Membrane Antigen | Type II membrane protein. 1/N-acetylated-alpha-linked acidic dipeptidase | Over-expressed in PCa compared to BPH and normal | Diagnostic. Imaging marker and target for therapy | Tissue, blood and urine | [52,53] |
GOLM1 | Golgi membrane protein 1 (GOLPH2) | Cis-Golgi membrane protein of unknown function | Over-expressed in PCa | Diagnostic | Urine | [54,55] |
GSTP1 | Glutathione S-transferase P1 | Enzyme involved in protecting DNA from free radicals | Loss of GSTP1 expression due to the promoter hypermethylation (>90% of PCa). Correlates with the number of cores found to contain PCa | Diagnostic (indicator for repeat biopsy) | Tissue and urine DNA | [56,57] |
HPN | Hepsin | Membrane serine protease | Over-expressed in 90% PCa tumors (highly produced in HGPIN and PCa compared with BPH) | Diagnostic | Tissue | [58,59] |
IL-6 | Interleukin-6 | Cytokine secreted by a variety of cell types, is involved in the immune and acute-phase response | Increased concentrations of IL-6 and IL-6R in metastatic and androgen-independent PCa | Diagnosis and Prognostic | Blood | [60–62] |
IMPDH2 | IMP (inosine 5′-monophosphate) dehydrogenase 2 | Myc target gene associated with nucleotide biosynthesis | Increased serum level associated with the clinicopathological features of the patients with PCa | Diagnostic | Blood | [63] |
KLK2 | Human Kallikrein 2 | Secreted serine protease | Over-expressed during PCa progression | Diagnostic and Prognostic | Tissue and blood | [64,65] |
KLK3 (PSA) | Kallikrein-related peptidase 3 (Prostate-Specific Antigen) | Secreted serine protease. Serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of PCa. | Increased expression associated with malignant PCa | Diagnostic | Blood, urine | [66] |
KLK4 | Kallikrein-related peptidase 4 | One of fifteen kallikrein subfamily members located in a cluster on chromosome 19 | Increased expression associated with malignant PCa | Prognostic | Tissue RNA and IHC | [67,68]. |
MAP3K5 | Mitogen-activated protein kinase kinase kinase 5 | Signaling cascade | Increased expression associated with PCa | Prognostic | Tissue RNA and IHC | [69] |
MKI67 | Encoding antigen identified by monoclonal antibody Ki-67 | Tumor growth marker, encodes a nuclear protein that is associated with and may be necessary for cellular proliferation | Increased expression associated with malignant prostate cancer | Prognostic | Tissue | [70–72] |
MMP26 | Matrix metallo peptidase 26 | Involved in the breakdown of extracellular matrix in normal physiological processes and cancer metastasis. | Highest expression in HGPIN and decline in cancer, possible involvement in formation of early cancer. | Progression | Tissue RNA | [73–76] |
MMP9 | Matrix metallo proteinase 9 | Implicated in invasion and metastasis of human malignancies | Over-expressed in PCa | Diagnostic | Urine | [77,78] |
OR51E2/PS GR | Prostate Specific G-coupled Receptor | Receptors coupled to heterotrimeric GTP-binding proteins | Over-expressed in PCa | Diagnostic | Tissue and urine | [79–81] |
PAP | Human Prostatic acid phosphatase | Enzyme | Over-expressed in PCa and in bone metastasis | Diagnostic and Prognostic of PCa bone metastasis | Blood and urine | [82,83] |
PCA3 | Prostate Cancer Gene 3 | Non coding mRNA | Prostate specific and highly up-regulated in PCa | Diagnostic (indicator for repeat biopsy) | Tissue and urine | [84–93] |
PDIA3 | Protein disulfide isomerase family A, member 3. | Endoplasmic reticulum that interacts with lectin chaperones calreticulin and calnexin to modulate folding of newly synthesized glycoproteins. | Increased expression associated with malignant PCa | Prognostic | Tissue RNA and IHC | [69] |
PSCA | Prostate Stem Cell Antigen | Membrane glycoprotein | Specific production in the prostate and possible target for therapy | Prognostic (correlated with higher Gleason score, higher stage, and the presence of metastasis) | Tissue and blood | [94,95] |
RARB | Retinoic acid receptor, beta | Binds retinoic acid. Mediates signalling in embryonic morphogenesis, cell growth and differentiation. | DNA methylation | Prognostic | Tissue and urine DNA | [96,97] |
RASSF1A | Ras association (RalGDS/AF-6) domain family member 1 | Potential tumor suppressor. Required for death receptor-dependent apoptosis | DNA methylation | Prognostic | Tissue and urine DNA | [97] |
Sarcosine | Sarcosine | N-methyl derivative of the amino-acid glycine | Seems to be differentially expressed metabolite elevated during PCa progression to metastasis | Prognostic | Urine and blood | [98] |
SPINK1 | Serine peptidase inhibitor, Kazal type 1 | Serine peptidase inhibitor | Overexressed in a portion of non-ETS translocated tumors | Diagnostic | Urine, tissue | [54,99] |
TERT | Telomerase reverse transcriptase | Maintains the telomeric ends of chromosomes and if telomerase is active, cancer cells may escape cell cycle arrest and replicative senscence | Amplification in PCa, significative association with Gleason score | Prognostic | Urine and blood | [57,100,101] |
TGFB1 | Transforming growth factor-b1 | Growth factor involved in cellular differentiation, immune response, angiogenesis, and proliferation | Role of TGFβ1 in PCa progression. | Prognostic (Correlation with tumor grade and stage and lymph node metastasis) | Tissue and blood | [62,102,103] |
TIMP4 | TIMP metallopeptidase inhibitor 4 | Inhibitors of the matrix metallo proteinases | Highest expression in HGPIN and decline in cancer, possible involvement in formation of early cancer. | Progression | Tissue RNA | [73–75] |
TMPRSS2:E RG | 5′ UTR of the prostate-specific androgen regulated transmembrane protease serine2 and v-ETS erythroblostosis virus E26 oncogene homolog | Gene fusion; androgen drives the expression of ETS-TF and causes tumor proliferation | The most common gene fusion in PCa. Over-expressed PCa and related to PCa aggressiveness | Prognostic for aggressive PCa and detection of PCa | Tissue and urine | [104–106] |
PLAU and UPAR | Plasminogen Activator, Urokinase and Receptor | Degradation of extra cellular matrix | Over-expressed in BPH and PCa vs benign | Prognostic (increased uPA and uPAR in PCa patients with bone metastasis) | Tissue and blood | [107,108] |
Biomarker type | Study | Marker | PCa/study | Sens. | Spec. | AUC |
---|---|---|---|---|---|---|
DNA | Hoque et al., 2005 [112] | p16, ARF, MGMT, GSTP1 | 73 | 87% | 100% | ND |
Rouprêt et al., 2007 [110] | GSTP1, RASSF1A, RARB, and APC | 95/133 | 87% | 89% | ND | |
Vener et al., 2008 [165] | GSTP1, RARB and APC | 54/121 | 55% | 80% | 0.69 | |
Payne et al., 2009 [166] | GSTP1, RASSF2, HIS1H4K, TFAP2E | 192 | 94% | 27% | ||
Baden et al., 2009 [164] | GSTP1, RARB and APC | 178/159 | ND | ND | 0.72 | |
Costa et al., 2011 [113] | PCDH17, TCF21 | 318 | 26% | 100% | ||
mRNA | Hessels et al., 2007 [104] | PCA3 and TMPRSS2:ERG | 78/108 | 73% | 52% | ND |
Laxman et al., 2008 [54] | PCA3, GOLPH2, SPINK1 and TMPRSS2:ERG | 152/257 | 66% | 76% | 0.76 | |
Ouyang et al., 2009 [167] | AMACR and PCA3 | 43/92 | 72% | 53% | ND | |
Talesa et al., 2009 [117] | PSMA, HPN, PCA3, GalNAC-T3 and serum PSA | 49% | ND | ND | ||
Rigau et al., 2010 [81] | PCA3 and PSGR | 73/215 | 96% | 34% | 0.73 | |
Rigau et al., 2011 [119] | PSMA, PSGR, PCA3 and serum PSA | 57/154 | 96% | 50% | 0.82 | |
Salami et al., 2011 [168] | PCA3, TMPRSS2:ERG and serum PSA | 15/45 | 80% | 90% | 0.88 | |
Jamasphvili et al., 2011 [169] | PCA3, AMACR, TRMP8, SMSB | 104 | 72% | 71% | ||
Nguyen et al., 2011 [170] | TMPRSS2:ERG subtypes | 101 | 35% | 100% | ||
Tomlins et al., 2011 [171] | PCA3 and TMPRSS2:ERG | 463 (acad.) and 439 (biopsy) | a_0.64 and b_0.66 | |||
Protein | Rehman et al., 2004 [154] | ENO1, IDH3B, B2M, A1M, PRO2044 and S100A9 (Calgranulin_B/MRP-14) | 6 PC (12) | |||
Theodorescu et al., 2005 [155] | Proteinpolypeptide | 26/47 | 92% | 96% | ||
M’Koma et al., 2007 [157] | 130 m/z | 89/407 | 81% | 80% | ||
Theodorescu et al., 2008 [156] | 12 protein pannel + age + serum PSA | 86 Training set + 213 validation set | 91% | 62% | ||
Okamoto et al., 2008 [158] | 72 masspicks | 57/113 | 91% | 83% | ||
Mixture | Cao et al., 2010 [172] | mRNA, protein and metabolite (PCA3, TMPRSS2: ERG, ANXA3, Sarcosine, and urine PSA) | 86/131 | 95% | 50% | 0.86 |
Prior et al., 2010 [173] | mRNA (AMACR/MMP2), DNA (GSTP1/RASSF1A) and PSA in serum and urine | 34/113 | 57% | 97% | 0.79 |
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Rigau, M.; Olivan, M.; Garcia, M.; Sequeiros, T.; Montes, M.; Colás, E.; Llauradó, M.; Planas, J.; De Torres, I.; Morote, J.; et al. The Present and Future of Prostate Cancer Urine Biomarkers. Int. J. Mol. Sci. 2013, 14, 12620-12649. https://doi.org/10.3390/ijms140612620
Rigau M, Olivan M, Garcia M, Sequeiros T, Montes M, Colás E, Llauradó M, Planas J, De Torres I, Morote J, et al. The Present and Future of Prostate Cancer Urine Biomarkers. International Journal of Molecular Sciences. 2013; 14(6):12620-12649. https://doi.org/10.3390/ijms140612620
Chicago/Turabian StyleRigau, Marina, Mireia Olivan, Marta Garcia, Tamara Sequeiros, Melania Montes, Eva Colás, Marta Llauradó, Jacques Planas, Inés De Torres, Juan Morote, and et al. 2013. "The Present and Future of Prostate Cancer Urine Biomarkers" International Journal of Molecular Sciences 14, no. 6: 12620-12649. https://doi.org/10.3390/ijms140612620
APA StyleRigau, M., Olivan, M., Garcia, M., Sequeiros, T., Montes, M., Colás, E., Llauradó, M., Planas, J., De Torres, I., Morote, J., Cooper, C., Reventós, J., Clark, J., & Doll, A. (2013). The Present and Future of Prostate Cancer Urine Biomarkers. International Journal of Molecular Sciences, 14(6), 12620-12649. https://doi.org/10.3390/ijms140612620