Table 1.

Selected candidate serum protein biomarkers with the potential of being detected within the diagnostic, prognostic and/or predictive stages of PCa.

Protein	Type	Biological Characteristics	Clinical Relevance	Normal Serum Level	PCa Cut-Off Level	PCa Purpose	Sample	Ref
Alpha- Methylacyl- CoA Racemase (AMACR)	Peroxisomal and mitochondrial racemase	Involved in the body’s fatty acid synthesis and metabolism	Overexpression in prostate cancer (PCa) tissues Potential for distinguishing benign prostatic hyperplasia (BPH) patients from PCa patients	-	10.6 ng/mL	Diagnostic/Prognostic	Serum, Tissue and Urine	[3,43,46,47,48,49,50,51]
Cluster of Differentiation (CD) -14	Glycoprotein	Inflammation marker Presented either as a membrane bound CD-14 or in its soluble form	Increased expression leads to elevated concentration of monocyte in BPH tissues compared to PCa tissues Linked to advanced PCa	1.9 µg/mL	-	Diagnostic	Serum and Tissue	[52,53,54,55]
Chromogranin- A (CgA)	Pro-hormone peptide	A part of the granin family of proteins Released by neuroendocrine (NE) cells in the prostate gland and used as a cell marker for endocrine and NE cells	High CgA serum levels seen in patients with PCa-resistant hormone therapy compared to patients with BPH and indolent PCa. PCa patients with higher CgA levels have lower prognosis and survival compared to those with lower CgA levels	-	-	Diagnostic/Prognostic	Serum	[39,43,45,46,47,56]
Early Prostate Cell Antigen (EPCA) -1	Nuclear matrix protein	Uncertain contribution to nuclear morphology	Linked to early carcinogenesis and to predict repeated biopsy	-	-	Diagnostic	Serum and Tissue	[2,3,39,43,46,48]
EPCA -2	Nuclear matrix protein	Uncertain contribution to nuclear morphology	Connected to early carcinogenesis Can differentiate between indolent PCa and aggressive PCa	-	-	Diagnostic/Prognostic	Serum	[2,3,39,43,46,48]
Golgi Membrane protein (GOLM)-1	Type II Golgi membrane protein	Aids for the transport of proteins through the Golgi Apparatus. Also known as Golgi phosphoprotein 2 (GOLPH2) or (GP73)	Up-regulation in patients with PCa PCa gene fusion protein Suggested to be an aggressive PCa predictor	54 ng/mL	-	Diagnostic/Prognostic	Serum, Tissue, and Urine	[48,52,57,58,59]
Human Kallikrein 2 (hK2)	Serine protease enzyme	Secreted by epithelial cells in the prostate gland 80% homologous to PSA but different in enzymatic activity Splits pro-PSA, producing PSA Also known as Kallikrein-related peptide 2 (KLK2)	Highly expressed in prostate tissue, especially as PCa progresses to advanced stages Studies have shown strong correlation with PCa-specific survival, but large cohort validation studies required	-	-	Diagnostic/Prognostic	Serum and Tissue	[31,35,39,43,45,46,47,49,50,60]
Insulin-like Growth Factor-1 (IGF-1)	Growth hormone-dependent polypeptides	Produced alongside IGFBP-3 Involved in multiple cellular growth-related responses, including synthesis of DNA, RNA, and cellular proteins	Elevated serum levels Associated with cancer development during subclinical disease stages Not a useful biomarker for early diagnosis or screening of PCa	160 ng/mL	-	Diagnostic	Serum	[39,43,45,47,49,52,55,61,62,63,64]
IGF-Binding Protein-3 (IGFBP-3)	Binding protein	Produced alongside IGF-1 Binds to approximately 75 to 90% of circulating IGF-1, in conjunction with the acid-labile subunit	Under-expressed in PCa patients Suggested to limit the availability of IGF-1 and regulate apoptosis Suggested to be a strong predictor of significant PCa compared to indolent PCa	3.7 µg/mL	-	Diagnostic/Prognostic	Serum	[39,45,52,55,62,63,64]
Interleukin-6 (IL-6) and Receptor (IL-6R)	Cytokine	Has variable effects on immune and hematopoietic mechanisms Produced at acute and chronic inflammation sites	Elevated levels in PCa cells Associated with metastatic and androgen independent PCa Predictors of disease extent in the progression and survival of PCa patients Soluble IL-6R has a stronger correlation to disease progression than IL-6	0.006–0.02 ng/mL	0.02–1 ng/mL	Prognostic/Predictive	Serum	[2,31,43,47,48,65,66,67,68,69]
Platelet Factor-4 (PF-4)	Chemokine	Belongs to the chemokine (CXC) family, ligand 4 (CXCL4) Released during stimulation of the platelet	Lower serum levels in metastatic PCa patients, compared with healthy or indolent/clinically insignificant PCa patients	5–10 μg/mL in serum (2–10 ng/mL in plasma)	10–500 ng/mL	Diagnostic	Serum	[52,68,70,71,72,73,74]
Prostatic Acid Phosphatase (PAP)	Glycoprotein enzyme	Also known as Acpp or prostatic specific acid phosphatase (PSAP) More research is needed to fully understand the biological role	Elevated in patients with PCa metastasizing to the bone Potential biomarker for PCa progressions and response of advanced PCa to androgen deprivation therapy	-	>2.0 ng/mL	Diagnostic/Prognostic	Serum and Urine	[32,45,48,75,76,77]
Prostate-Specific Antigen (PSA)	Serine protease enzyme	Also known as Kallikrein-related peptidase 3 (KLK3) or human kallikrein 3 (hK3) Specifically produced by epithelial cells in the prostate gland Has the biological role of seminal fluid liquefaction Androgen-regulated by androgen response elements	Increased expression within the prostate gland Widely known PCa biomarker; however lacking in sensitivity and specificity	1–4 ng/mL	4.0 ng/mL	Diagnostic/Prognostic/Predictive	Serum and Urine	[35,39,45,47,48,52,68,69,75,78]
Prostate-Specific Membrane Antigen (PSMA)	Type II integral membrane glycoprotein with cell surface carboxypeptidase function	Expressed in the epithelial cells of the prostate Also known as Folate hydrolase 1, which has the function of folate hydrolase Involved in cell stress reaction, signal transduction, cell migration, and nutrient uptake	Highly expressed in PCa cells compared to BPH and normal cells Suggested role in PCa progression	200–300 ng/mL	300–650 ng/mL [68,69] or 349.4–946.6 ng/mL [79]	Diagnostic/Prognostic	Serum and Urine	[2,43,46,47,48,49,52,60,68,69,79]
Prostate Stem Cell Antigen (PSCA)	Membrane glycoprotein	Specifically produced in the prostate gland Involved in the regulation of cell proliferation	Possible therapy target Increased expression associated with higher Gleason score, higher stage and in the presence of aggressive PCa	-	-	Prognostic	Serum and Tissue	[2,46,48,49]
Testosterone	Steroid hormone	Involved in the development and preservation of prostate gland and seminal vesicles Significant role in sexual development and anabolism Acts on endocrine signal transduction	Androgen receptor ligand associated with. The spread of PCa Higher levels in aggressive than indolent cancer patients More research needed to fully understand its clinical relevance	-	-	Prognostic/Predictive	Serum	[43,45,46,78]
Transforming Growth Factor- ß1 (TGF-ß1)	Cytokine	Growth factor Involved in cell proliferation, immune response, differentiation, and angiogenesis	Suggested promotion of PCa cell progression Associated with higher tumor grade, tumor invasion and metastasis in PCa patients	-	-	Prognostic	Serum	[2,31,43,47,49,50]
Urokinase Plasminogen Activator (uPA) and Receptor (uPAR)	Serine protease and transmembrane receptors	Plasminogen activator, converting plasminogen into plasmin Plasmin activates protases associated with the degradation of extracellular matrix	Highly expressed in PCa and BPH patients compared to healthy patients Correlated with aggressive PCa recurrences Suggested as a predictor of biochemical progression following surgery	-	-	Diagnostic/Prognostic	Serum and Tissue	[2,31,39,43,47,48,50,80,81]
Vascular Endothelial Growth Factor (VEGF)	Dimeric, heparin-binding protein	Vital endothelial cell growth factor in controlling the angiogenesis of the tumor and increase vascular permeability	Elevated concentration in PCa patients Suggested PCa angiogenesis	657 (±43) pg/mL for VEGF-D ligand	-	Prognostic	Serum	[43,52,55,66,82,83]