Introduction
Prostate cancer is the most commonly diagnosed cancer in men and in 2020 accounted for an estimated 23,300 new cancer cases and more than 4,200 mortalities in Canada 1,Reference Brenner, Weir and Demers2 and about 238,590 new cancer cases and 29,720 deaths in the United States of America. Reference Siegel, Miller and Jemal3 The current standard and definitive diagnosis of the disease is via prostate biopsy; however, the decision on when to biopsy a patient with non-suspicious digital rectal examination (DRE) result and total prostate-specific antigen (PSA) in the 4–10 ng/mL range can be challenging since about two-thirds of such biopsies are typically found to be benign. Reference White, Shenoy and Tutrone4,Reference Osei and Swanson5 Kremer et al. Reference Kremer, Klein and Mendelson6 reported that screening, diagnosis and treatment options for gland-confined prostate cancers are also complicated due to the lack of prognostic tools capable of discriminating between aggressive and non-aggressive cancers. At present, serum PSA level is the most commonly used test for the detection of prostate cancer, although these levels can also be elevated in benign conditions, have limited specificity and result in high rates of overdiagnosis and treatment of a significant number of indolent disease. Reference Osei and Swanson5,Reference Hendriks, van Oort and Schalken7–Reference Osei, Swanson and Francis11 According to Hessels et al., Reference Hessels, van Gils and van Hooij12 PSA-based opportunistic screening has led to an increase in prostate cancer overdiagnosis and overtreatment due to the high incidence of clinically insignificant disease. Therefore, in order to shift the treatment paradigm of prostate cancer towards more patient-specific and targeted therapy, there is a need for a clear system that makes its detection binary so as to minimise the rate of inaccurate detections. Reference Osei and Swanson5,Reference Osei, Swanson and Francis11,Reference Osei, Lumini and Gunasekara13,Reference Osei, Walters and Masella14 Consequently, several studies have investigated the potential of new biomarkers capable of improving prostate cancer diagnosis, prognosis and treatment prediction to help avoid unnecessary biopsies and to discriminate aggressive from slow-growing cancers, thus avoiding overtreatment. Reference White, Shenoy and Tutrone4,Reference Kremer, Klein and Mendelson6–Reference Alford, Brito, Yadav, Yadav, Tewari and Renzulli10,Reference Hessels, van Gils and van Hooij12,Reference Vanaja, Cheville, Iturria and Young15–Reference Li, Stovall, Wang and Sui105 Biomarkers commonly used for diagnosis, prognostication and therapeutic monitoring can be obtained through either liquid or tissue biopsies and the conventional tissue biopsies are typically surgical biopsy, radiologically guided biopsy or endoscopic biopsy. According to Osei et al., Reference Osei, Lumini and Gunasekara13,Reference Osei, Walters and Masella14 understanding the molecular mechanisms and signalling pathways of biomarkers can potentially lead to more personalised and targeted treatment via therapeutic targeting of specific genetically aberrant pathways which play key roles in cancer formation and may provide optimal treatment choices in clinical practice. In a previous study, Osei and Swanson Reference Osei and Swanson5 presented a comprehensive literature review of currently available clinical biomarkers and more recently, Osei et al. Reference Osei, Swanson and Francis11 reported on novel and promising liquid-based biomarkers for the management of prostate cancer. In this narrative review paper, we describe 11 novel and promising tissue-based prostate cancer biomarkers used in risk assessment, screening for early detection and diagnosis, identification of patients’ risk for metastatic disease and subsequent relapse, monitoring patient response to specific treatment and to provide clinicians the potential of prospectively identifying groups of patients who will benefit from a particular treatment.
Materials and Methods
The following databases; PubMed, PMC, NCBI, PNAS, Springer Link, Wiley Online Library, Lacent, Science Direct, Medline were searched from August to December 2020 for relevant studies published in English between 2000 and 2020 and reporting on potential biomarkers for diagnostic, predictive, prognostic and therapeutic monitoring of prostate cancer. The literature search used the following keywords: ‘emerging biomarkers and prostate cancer’, ‘prostate cancer biomarkers’, ‘tissue-based biomarkers for prostate cancer’, ‘tissue-based biomarkers’, ‘biomarkers for prostate cancer’, ‘novel biomarker and prostate cancer’. The searches were not limited by study design and included conference abstracts, full research articles and reviews. Several publications on prostate cancer biomarkers used for disease management were identified and we excluded articles that reported on currently available clinical biomarkers and novel liquid-based biomarkers. For the current paper, we reviewed articles that reported on novel and promising tissue-based biomarkers for prostate cancer management.
Zinc finger protein 154 (ZNF154)
The ZNF154 gene is a protein-coding gene located on the long arm of chromosome 19 at position 13.43 (19q13.43) and encodes a protein belonging to the zinc finger Kruppel family of transcriptional regulators. Reference Sánchez-Vega, Gotea and Petrykowska16,Reference Tommerup and Vissing106,Reference Urrutia107 According to Sánchez-Vega et al. Reference Sánchez-Vega, Gotea and Petrykowska16 and Zhang et al., Reference Zhang, Shu and Wang17 functional enrichment analysis shows that ZNF154 is involved in biological processes and molecular functions such as biological regulation, metabolic processes, response to the stimulus, multicellular organismal processes, cell communication and proliferation, protein and ion binding and transferase activities. According to Szeliski et al., Reference Szeliski, Adamowicz, Gastecka, Drewa and Pokrywczyńska18 ZNF154 expression is downregulated in prostate cancer, has a high predictive value to discriminate benign prostatic hyperplasia (BPH) from prostate cancer and is a potential specific marker for the diagnosis of the disease. The methylation level of ZNF154 is also reported to be associated with androgen receptor activity, which suggests that it may promote the progression of prostate cancer, and thereby could play an important role in the disease development and potentially a new therapeutic target for prostate cancer. Reference Zhang, Shu and Wang17–Reference Mahapatra, Klee and Young19
Zhang et al. Reference Zhang, Shu and Wang17 screened 87 methylated genes for early diagnosis and prediction of biochemical recurrence in prostate cancer patients using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. They also evaluated ZNF154 expression level by quantitative real-time polymerase chain reaction (qRT-PCR) and assessed its prognostic potential. They reported that ZNF154 has three hypermethylation sites (cg03234186, cg12506930, cg26465391) in the promoter region in prostate cancer tissues, has lower expression levels in prostate cancer tissues than in benign prostate tissues and is an independent factor for biochemical recurrence prediction. Furthermore, they reported that ZNF154 methylation level is negatively correlated with messenger ribonucleic acid (mRNA) expression, highly prostate cancer-specific, associated with biochemical recurrence, positively correlated with androgen receptor activity and its hypermethylation is associated with advanced tumour stage. Reference Zhang, Shu and Wang17
Hepsin (HPN)
The Hepsin (HPN) gene, first identified in the late 1980s, is a type II transmembrane cell surface serine protease normally expressed during development and is absent or in low expression levels in normal prostate or BPH. Reference Kelly, Setlur and Ross20–Reference Wu and Parry24 It is reported to be overexpressed in about 90% of prostate cancers and has been identified as one of the most upregulated genes in the disease, although the functional significance of the upregulation is unknown. Reference Klezovitch, Chevillet, Mirosevich, Roberts, Matusik and Vasioukhin21,Reference Wu and Parry24,Reference Tang, Mahajan and Nguyen25 According to Kelly et al., Reference Kelly, Setlur and Ross20 HPN is expressed in both high-grade prostate intraepithelial neoplasia and in hormone-refractory metastatic tumours. Tang et al. Reference Tang, Mahajan and Nguyen25 have reported that the expression level of HPN increases early in the initiation of prostate cancer and its overexpression promotes disease metastasis especially to the bone marrow and is maintained throughout progression and metastasis. According to Kelly et al., Reference Kelly, Setlur and Ross20 the cell surface expression and malignant cell localisation of HPN make it an ideal marker for the development of prostate cancer-targeted imaging agents and Magee et al. Reference Magee, Araki and Patil22 reported that HPN overexpression in prostate cancer also makes it a potential drug target for treatment. The expression level of HPN is reported to correlate with a high Gleason score and indicative of poor clinical outcome and relapse after prostatectomy. Reference Tang, Mahajan and Nguyen25 According to Wu and Parry, Reference Wu and Parry24 the upregulation of HPN correlates with disease progression and its overexpression promotes cancer progression and metastasis, however, application of anti-HPN antibodies inhibits the invasion of prostate cancer cells. Other studies have also reported an association between decreased HPN expression in hormone-refractory metastatic prostate cancer and elevated PSA levels in cancer patients. Reference Kelly, Setlur and Ross20,Reference Srikantan, Valladares, Rhim, Moul and Srivastava23,Reference Tang, Mahajan and Nguyen25
The significance of HPN in prostate cancer has been investigated by several independent studies analysing consistent gene expression pattern differences between prostate cancer and benign or normal prostate tissues. Reference Kelly, Setlur and Ross20–Reference Srikantan, Valladares, Rhim, Moul and Srivastava23,Reference Tang, Mahajan and Nguyen25 Kelly et al. Reference Kelly, Setlur and Ross20 investigated the development of potential HPN-targeted imaging probes for improved detection of prostate cancer. They reported that HPN-targeted imaging may provide a new approach for improved detection of prostate cancer and would be useful in all stages of the disease spanning from pre-diagnosis to the delineation of non-localised disease to post-therapy detection of disease recurrence, and would significantly impact the diagnosis and treatment of the disease. Klezovitch et al. Reference Klezovitch, Chevillet, Mirosevich, Roberts, Matusik and Vasioukhin21 investigated the role of HPN in prostate epithelium in vivo and reported that its overexpression in prostate epithelium in a mouse model causes disorganisation of the basement membrane and promotes primary prostate cancer progression and metastasis to liver, lung and bone. Magee et al. Reference Magee, Araki and Patil22 also investigated the expression profiles of benign and malignant prostate tissue specimens of different histological grades and clinical stages to identify genes that are differentially expressed between benign and malignant glands. They observed overexpression of HPN in prostate carcinoma cells and reported that its molecular properties make it an ideal target for prostate cancer treatment. Furthermore, they reported that the significant difference between HPN expression in benign glands and malignant tissues suggests that prostate cancer would be extremely sensitive to HPN inhibitors. Srikantan et al. Reference Srikantan, Valladares, Rhim, Moul and Srivastava23 investigated the effects of overexpression of HPN in metastatic prostate cancer cells with or without endogenous HPN expression to study the mechanisms and functional consequences of HPN expression in the disease. They reported that low expression of HPN or loss of expression is associated with poor prognosis and suggested that its expression is a potential therapeutic target of prostate cancer. Tang et al. Reference Tang, Mahajan and Nguyen25 conducted a study on the development, analysis and animal trial of a novel, non-toxic and orally bioavailable small molecule HPN inhibitor (HepIn-13). They reported that, in a preclinical murine model of metastatic prostate cancer, long-term exposure to the HPN inhibitor blocks disease progression and inhibits bone, liver and lung metastasis.
Aurora kinases
The aurora kinases are a family of serine–threonine kinases, of which only Aurora-A (AURKA), Aurora-B (AURKB) and Aurora-C (AURKC) are found in mammalian cells. Reference Boss, Beijnen and Schellens26–Reference Buschhorn, Klein and Chambers30 The human AURKA, AURKB and AURKC genes are located on the long arm of chromosome 20 at position 13.2 (20q13.2), on the short arm of chromosome 17 at position 13.1 (17p13.1) and on the long arm of chromosome 19 at position 13.43 (19q13.43) and encode the AURKA, AURKB and AURKC proteins, respectively. Reference Boss, Beijnen and Schellens26,Reference Lee, Frolov, Li, Ayala and Greenberg28,Reference Buschhorn, Klein and Chambers30–Reference Mankovska, Gerashchenko and Rozenberg34 These genes are reported to play an essential role in the mitotic pathway and also ensure correct chromosome assembly, formation of the mitotic spindle and cytokinesis. Reference Boss, Beijnen and Schellens26,Reference Lee, Frolov, Li, Ayala and Greenberg28,Reference Buschhorn, Klein and Chambers30 According to Lee et al., Reference Lee, Frolov, Li, Ayala and Greenberg28 AURKA is essential for mitotic spindle formation and accurate chromosome segregation, whereas AURKB is a chromosome passenger protein kinase that regulates centrosome separation, chromosome segregation and cytokinesis. The aberrant expression of AURKA and AURKB has been reported to induce aberrant mitosis, centrosome irregularities and chromosomal instability which lead to aneuploidy and cell transformation. Reference Lee, Frolov, Li, Ayala and Greenberg28 The overexpression of AURKA and AURKB in prostate cancer has been observed by several investigators and is reported to lead to cytokinesis failure causing tetraploidy and multinucleation, which is associated with centrosome amplification. Reference Lee, Frolov, Li, Ayala and Greenberg28,Reference Buschhorn, Klein and Chambers30,Reference Bar-Shira, Pinthus and Rozovsky35–Reference Qu, Huang and Li37 Pihan et al. Reference Pihan, Purohit, Wallace, Malhotra, Liotta and Doxsey38 have reported that all prostate cancers show centrosome defects, which increases with increasing Gleason grade and genomic instability. According to Buschhorn et al., Reference Buschhorn, Klein and Chambers30 the amplification of centrosomes is associated with elevated AURKA expression and is found with aberrant mitotic divisions leading to genomic instability and aneuploidy, and eventually, tumourigenesis. Furthermore, they reported that the correlation of AURKA with duplicated centrosomes suggests that AURKA overexpression may be a marker of genetic instability contributing to prostate cancer development. Reference Buschhorn, Klein and Chambers30 According to Boss et al., Reference Boss, Beijnen and Schellens26 overexpression of AURKA and AURKB has been associated with poor prognosis in cancer patients, whereas AURKC overexpression has not been implicated in tumourigenesis.
Buschhorn et al. Reference Buschhorn, Klein and Chambers30 investigated AURKA overexpression in high-grade prostatic intraepithelial neoplasia (PIN) lesions and prostate cancer using immunohistochemistry. They observed AURKA overexpression in 96% of high-grade PIN cases, 98% of prostate cancer cases and 29% of cases with normal glands from cancerous prostates. They concluded that AURKA is overexpressed in some normal prostate tissue and most high-grade PIN lesions, suggesting that its overexpression may be an early event that leads to genetic instability in prostate carcinogenesis Reference Buschhorn, Klein and Chambers30 Lee et al. Reference Lee, Frolov, Li, Ayala and Greenberg28 also investigated the overexpression of AURKA and AURKB in human PC3 and LNCaP and mouse C1A prostate cancer cell lines, as well as the relationship between AURKA and AURKB expression patterns with tumourigenicity, clinical staging, surgical margin status and seminal vesicle invasion and evaluated the efficacy of the aurora kinase inhibitor VX680 on cell viability. They examined immunostained tissue microarrays from human samples of non-neoplastic prostate, PIN lesions and prostate tumours using qRT-PCR. They observed overexpression of AURKA and AURKB in the cell lines, PIN lesions and prostate tumours compared with the non-neoplastic samples. Furthermore, they reported correlations between AURKA expression in non-neoplastic prostates with seminal vesicle invasion and in prostate tumours with positive surgical margins. In addition, they also observed that nuclear expression of AURKB in PIN lesions is correlated with clinical staging of the tumour, whereas cytoplasmic expression in tumours is correlated with seminal vesicle invasion. They also reported decreased prostate cancer cell survival when cell lines were treated with VX680, and the addition of doxorubicin significantly enhanced the potency of the chemotherapy drug. Reference Lee, Frolov, Li, Ayala and Greenberg28 Qu et al. Reference Qu, Huang and Li37 conducted a study to identify microRNAs (miRNAs) targeted to AURKA and to determine their impact on prostate cancer progression by measuring miR-199a-3p levels with methylation-specific quantitative RT-PCR and AURKA levels with Western blot analysis. They used human samples of benign and tumour tissue from prostate cancer patients and a xenograft mouse model created by transplanting human prostate cancer cell line DU145 cells into nude mice. They reported that miR-199a-3p is downregulated in human prostate tumour tissue compared to normal tissue and its expression pattern is inversely correlated with the expression pattern of AURKA as well as tumour stage and Gleason score of prostate cancer. Furthermore, they observed that mice treated with miR-199a-3p agomir showed inhibited AURKA expression and xenograft prostate tumour growth, suggesting a novel mechanism for oncogene inhibition by miRNA-mediated pathways, which can potentially offer new strategies for prostate cancer treatment. Reference Qu, Huang and Li37
Mammalian target of rapamycin (mTOR)
The human mammalian target of rapamycin (mTOR) gene is located on the short arm of chromosome 1 at position 36.22 (1p36.22). It encodes the mTOR protein, which is a serine–threonine kinase in the phosphatidylinositol 3-kinase (PI3K)-related family and was initially discovered as the drug target of rapamycin. Reference Rad, Murray and Tee39–Reference Grunwald, DeGraffenried, Russel, Friedrichs, Ray and Hidalgo41 According to Rad et al., Reference Rad, Murray and Tee39 mTOR is a key promoter of cell growth and proliferation and functions as two distinct complexes: namely, the rapamycin-sensitive mTOR complex 1 (mTORC1), which is a positive regulator of cell growth and proliferation, and the less understood rapamycin-insensitive mTOR complex 2 (mTORC2). Studies have reported that mTOR is aberrantly activated in over 70% of cancers and atypical mTOR signalling in cancer is commonly the result of mutations in upstream inhibitors or activators. Reference Rad, Murray and Tee39,Reference Forbes, Bindal and Bamford42 Others have reported that mouse models suggest that mTOR (a downstream effector molecule of the PI3K pathway) is important in the development of prostate cancer, where it plays a pivotal role in forming precursor lesions such as high-grade PIN. Reference Rad, Murray and Tee39,Reference Sutherland, Pe Benito, Henshall, Horvath and Kench43 Several investigators have observed that phosphorylated-mTOR (p-mTOR, the activated state of mTOR) is overexpressed in prostate cancer growth and cell cycle progression. Reference Kremer, Klein and Mendelson6,Reference Sutherland, Pe Benito, Henshall, Horvath and Kench43–Reference Deeb, Gao, Jiang, Dulchavsky and Gautam45 Jiang and Liu Reference Jiang and Liu40 reported that the mTOR signalling pathway has been implicated in chemotherapy drug resistance, and experimental models and clinical trials have also shown that treatment with rapamycin (an mTOR inhibitor) in conjunction with other therapeutic agents has synergistic effects in tumour growth inhibition.
Brown et al. Reference Brown, Zotalis, Zhang and Zhao44 used a morphoproteomic approach to investigate the expression level of mTOR in 64 primary untreated prostate tumours, 20 high-grade PIN and 15 non-neoplastic prostatic glandular epithelium specimens. They reported moderate to strong cytoplasmic/plasmalemmal expression of p-mTOR in 93% of prostate cancer and in 100% of high-grade PIN specimens. They also reported a constitutive activation of the mTOR pathway in prostate cancer and high-grade PIN, with relative overexpression of p-mTOR in high-grade PIN. They concluded that the relative overexpression of p-mTOR in high-grade PIN has both pathogenetic and therapeutic implications that could be exploited to help prevent the development of invasive disease. Reference Brown, Zotalis, Zhang and Zhao44 Sutherland et al. Reference Sutherland, Pe Benito, Henshall, Horvath and Kench43 conducted a study to determine whether the expression of p-mTOR changes early in prostate cancer development. They evaluated p-mTOR expression in non-neoplastic tissue, PIN, high-grade PIN and prostate tumours via immunohistochemistry on tissue microarrays constructed from 120 archival formalin-fixed paraffin-embedded radical prostatectomy tissue specimens. They reported p-mTOR expression levels in all specimens with the least expression in non-neoplastic tissue, followed by PIN and high-grade PIN and the highest expression in diseased samples. Furthermore, they observed no significant increase in p-mTOR expression between high-grade PIN and proliferative inflammatory atrophy and reported that high p-mTOR expression correlated with a worse prognosis. They concluded that p-mTOR signalling has a potential role in both the initiation and progression of prostate cancer and that p-mTOR might be a potential target for chemoprevention in high-risk cancer patients. Reference Sutherland, Pe Benito, Henshall, Horvath and Kench43
Cyclin D1 (CCND1)
Cyclins are a family of regulatory proteins that control the progression of the cell cycle and activate cyclin-dependent kinases (CDKs), which control cell cycle processes through phosphorylation. There are five main classes of mammalian cyclins viz. the cyclin A (A1), cyclin B (B1 and B2), cyclin C, cyclin D (D1, D2 and D3) and cyclin E (E1 and E2), each with different functions in the cell cycle. The cyclin D1 (CCND1) gene is located on the long arm of chromosome 11 at position 13 (11q13) and encodes for the synthesis of cyclin D1 during the G1 phase of the cell cycle. Reference Moreno-Bueno, Rodríguez-Perales and Sánchez-Estévez46 The cyclin D1 gene is a key regulator in cell cycle progression and is known to be one of the most amplified chromosomal regions in human carcinomas. Reference Nakamura, Felizola and Kurotaki47 Activation of cyclin D1-CDK4/CDK6 phosphorylates the retinoblastoma protein and inactivates the protein’s tumour suppressive activity, thereby promoting cell cycle transition from the G1 to the S phase. Reference Moreno-Bueno, Rodríguez-Perales and Sánchez-Estévez46,Reference Casimiro, Di Sante and Ju48–Reference Tashiro, Tsuchiya and Imoto53 Consequently, disruption of cyclin D1 expression levels plays an important role in tumourigenesis. Reference Musgrove, Caldon, Barraclough, Stone and Sutherland50,Reference Tashiro, Tsuchiya and Imoto53,Reference Drobnjak, Osman, Scher, Fazzari and Cordon-Cardo54 Qie and Diehl Reference Qie and Diehl52 reported that overexpression of cyclin D1 results in dysregulated CDK activity, rapid cell growth under conditions of restricted mitogenic signalling, the bypass of key cellular checkpoints, and eventually, neoplastic growth. Furthermore, other studies have also reported that overexpression of cyclin D1 shortens the G1 phase of the cell cycle, suggesting that cyclin D1 overexpression by transcriptional, translational and post-translational deregulations can induce tumour growth. Reference Moreno-Bueno, Rodríguez-Perales and Sánchez-Estévez46,Reference Casimiro, Di Sante and Ju48,Reference Qie and Diehl52,Reference Tashiro, Tsuchiya and Imoto53 Overexpression of cyclin D1 is observed in human prostate carcinomas and various studies have been conducted to understand the effects of cyclin D1 expression on prostate tumour progression and to determine cancer-specific therapy. Reference Moreno-Bueno, Rodríguez-Perales and Sánchez-Estévez46,Reference Nakamura, Felizola and Kurotaki47,Reference Musgrove, Caldon, Barraclough, Stone and Sutherland50,Reference Tashiro, Tsuchiya and Imoto53 Marampon et al. Reference Marampon, Gravina and Ju55 reported that in vivo and in vitro silencing of cyclin D1 in PC3 and 22Rv1PCa prostate cell lines showed many cells arrested in the G1 phase of the cell cycle, independent of androgen receptor expression. Musgrove et al. Reference Musgrove, Caldon, Barraclough, Stone and Sutherland50 suggested that targeting cyclin D1 degradation by knockdown of USP2, a deubiquitinating enzyme specifically targeting cyclin D1, could be an effective therapeutic mechanism to inhibit cancer cells overexpressing cyclin D1 from proliferating. Qie and Diehl Reference Qie and Diehl52 also suggested that targeting CDK4/CDK6 to regulate cyclin D1-mediated cell cycle progression is a less challenging therapeutic target since cyclin D1 does not possess enzymatic activity. Musgrove et al. Reference Musgrove, Caldon, Barraclough, Stone and Sutherland50 and Qie and Diehl Reference Qie and Diehl52 showed that cyclin D1 upregulation is dependent on the loss of miRNAs that control cyclin D1 mRNA stability in prostate cancer. Similarly, Musgrove et al. Reference Musgrove, Caldon, Barraclough, Stone and Sutherland50 reported that most common cancers with cyclin D1 overexpression have higher rates of mRNA and protein expression in comparison to cyclin D1 amplification.
Casimiro et al. Reference Casimiro, Di Sante and Ju48 investigated the significance of cyclin D1 in androgen-induced DNA damage repair using human prostate cancer cells, LNCaP and NIH2/4 and PEC prostate epithelial cells from cyclin D1 knockout mice. They reported that cyclin D1 promotes dihydrotestosterone (DHT)-dependent DNA synthesis and is required for DHT-induced reduction of γH2AX foci in prostate cancer cell lines. He et al. Reference He, Franco and Jiang49 used a tissue recombination model to study the effects of controlled cyclin D1 expression in prostate epithelial and stromal cells that led to prostate tumour progression. They also examined prostatic epithelial cells isolated from human prostate tissue (BPH-1), a non-neoplastic prostate epithelial cell and its two cancerous derivatives (BPHCAFTD1 and BPHCAFTD2). They reported that cancerous prostatic epithelial cell lines expressed high levels of cyclin D1 and modified expression of cyclin D1 in noncancerous tissue showed initiation of cancer cell proliferation. They concluded that cyclin D1 overexpression increases tumour growth and its oncogenic abilities might be dependent on the tissue type. Comstock et al. Reference Comstock, Revelo, Buncher and Knudsen56 studied the effects of cyclin D1 and its correlation to PSA levels. They used immunohistochemical staining to examine 38 non-neoplastic prostate samples, 138 human prostate carcinomas and 3 lymph node metastatic specimens. They reported elevated cyclin D1 levels in neoplastic prostate cells in comparison to non-neoplastic cells and cyclin D1 levels correlated with tumour grade.
Fibronectin 1 (FN1)
Fibronectin 1 (FN1) is a glycoprotein found in the extracellular matrix (ECM) that plays an important role in cell adhesion, migration, differentiation and growth by binding to different types of receptors or ECM proteins. FN1 is found as a soluble form in the plasma or as an insoluble form in the ECM. Reference Bae, Kim, Kim, Choi, Kang and Lee57–Reference Wang and Hielscher59 The FN1 gene is found on the long arm of chromosome 2 at position 35 (2q35) and encodes for the synthesis of the FN1 protein. Plasma FN1 is produced by hepatocytes, whereas cellular FN1 is produced by different mesenchymal, benign and malignant epithelial cells. Reference Bae, Kim, Kim, Choi, Kang and Lee57 Cellular FN1 is deposited as filaments into the ECM, which is a protein-rich microenvironment that supports different cellular processes, and is widely distributed in malignant tumours and changes in the ECM environment, such as protein expression levels, play an important role in tumour progression. Reference Bae, Kim, Kim, Choi, Kang and Lee57 Among the ECM proteins, FN1 governs the inhibition and promotion of cancerous cell adhesion to nearby tissue through its expression levels and interaction with different receptors Reference Waalkes, Atschekzei and Kramer58–Reference Fornaro, Plescia and Chheang61 and according to Wang et al., Reference Wang and Hielscher59 integrin engagement plays a crucial role in FN1-mediated tumour cell invasion. Bae et al. Reference Bae, Kim, Kim, Choi, Kang and Lee57 and Sponziello et al. Reference Sponziello, Rosignolo and Celano62 reported that overexpression of FN1 is observed during the epithelial–mesenchymal transition (EMT, which is the transition from epithelial cells to mesenchymal cells) and this EMT is associated with tumour progression, invasion of surrounding tissue and chemoresistant characteristics. Reference Bae, Kim, Kim, Choi, Kang and Lee57,Reference Sponziello, Rosignolo and Celano62 It has also been reported for several tumours that the overexpression of FN1 is dependent on the deregulation of the integrins α5 and β1 as FN1 forms a complex with α5 and β1 in the ECM. High levels of FN1 are observed in prostate cancer and several other cancers and elevated FN1 expression levels have been shown to promote tumour growth, migration and invasion. Reference Wang and Hielscher59,Reference Fornaro, Plescia and Chheang61–Reference Ruiz-Garcia, Scott and Machavoine64 According to Jerhammar et al. Reference Jerhammar, Ceder, Garvin, Grénman, Grafström and Roberg63 and Wang and Hielscher, Reference Wang and Hielscher59 FN1 could be a potential biomarker to determine radioresistance to therapy in patients who show FN1 overexpression.
Jia et al. Reference Jia, Entersz, Butler and Foty65 investigated the relationship between cohesion, invasiveness and fibronectin matrix assembly (FNMA) in JHU-3, MAT-LyLu and AT-2 prostate cancer cell lines that are differentially invasive and metastatic. They reported that the cell lines expressed different levels of cohesion which is inversely related to invasiveness, and that invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Furthermore, they reported that wild-type α5 integrin promotes aggregate compaction, increases cohesion and reduces invasion of more aggressive cells and also that fibronectin matrix is a potential invasion suppressor of prostate cancer cells. They concluded that targeting restoration capacity for FNMA can increase tumour intercellular cohesion and act to suppress tumour cell detachment and subsequent invasion which could be exploited for the development of therapeutic methods to impact the early stages in the metastatic cascade of prostate cancer. Reference Jia, Entersz, Butler and Foty65 Moroz et al. Reference Moroz, Delella, Lacorte, Deffune and Felisbino66 conducted a study to determine whether culture conditions containing FN1 can modify the expression of matrix metalloproteinases (MMP)-2 and MMP-9 in human prostatic epithelial cell lines RWPE-1, LNCaP and PC3. They reported that RWPE-1 cells express detectable amounts of MMP-9, whereas the addition of FN1 induced high expression levels of MMP-2 in all cell lines. They concluded that FN1 exposure increases MMP-2 activity in the cell lines and that normal and tumour prostate cell lines express MMP-2 activity when in contact with FN1. Reference Moroz, Delella, Lacorte, Deffune and Felisbino66 Docheva et al. Reference Docheva, Padula, Schieker and Clausen-Schaumann67 investigated the effect of FN1 on cell adhesion, cell elasticity and cytoskeletal organisation of prostate cancer cells in human prostate cancer PC3 and LNCaP cell lines. They concluded that normal prostate cells are stiffer than prostate cancer cells and therefore cell elasticity has potential as a biomarker for prostate cancer detection.
Cluster of differentiation 73 (CD73)
Cluster of Differentiation 73 (CD73), also known as ecto-5'-nucleotidase (NT5E), is a glycosylphosphatidylinositol-anchored ectoenzyme encoded by the CD73 gene, which is located on the long arm of chromosome 6 at position 14.3 (6q14.3). Reference Hay, Sult and Huang68–Reference Beavis, Stagg, Darcy and Smyth73 CD73 is expressed on endothelial and epithelial cells, lymphocytes and leukocytes, as well as tumour cells and is involved in essential physiological and pathophysiological processes including cellular adhesion, signal transduction, endothelial homeostasis, epithelial ion and fluid transport, vascular inflammation, ischaemia, hypoxia and reperfusion injury. Reference Hay, Sult and Huang68–Reference Beavis, Stagg, Darcy and Smyth73 According to Zandieh et al., Reference Zandieh, Milani, Mohammadi and Hashemi70 CD73 is a cell adhesion molecule that mediates lymphocyte adhesion to endothelium and other studies Reference Hay, Sult and Huang68,Reference Ghalamfarsa, Kazemi and Mohseni69,Reference Yang, Du and Zu71,Reference Beavis, Stagg, Darcy and Smyth73,Reference Leclerc, Charlebois and Chouinard74 have also reported that it mediates the conversion of extracellular adenosine monophosphate into adenosine through the purinergic signalling pathway. Several studies have reported CD73 overexpression in many different cancer types including prostate cancer and the overexpression is associated with immune suppression, tumour growth, migration, invasion, angiogenesis and metastasis. Reference Ghalamfarsa, Kazemi and Mohseni69–Reference Beavis, Stagg, Darcy and Smyth73 According to Zandieh et al., Reference Zandieh, Milani, Mohammadi and Hashemi70 CD73 overexpression promotes the growth of cancerous cells, whereas other investigations Reference Hay, Sult and Huang68,Reference Wang, Tang and Wang72,Reference Leclerc, Charlebois and Chouinard74 observed that molecular inhibition of CD73 with small molecules or antibodies inhibits tumour formation, growth and metastasis, increases infiltration of CD8 + T cells and reduces immunosuppression of effector immune cells within the tumour. According to Hay et al., Reference Hay, Sult and Huang68 CD73 plays a major role in mediating the inhibitory function of regulatory B and T lymphocytes 2 as well as in maintaining endothelial integrity. Zandieh et al. Reference Zandieh, Milani, Mohammadi and Hashemi70 reported that clinical trials targeted CD73 therapy with monoclonal antibody (mAbs) anti-CD73 and small molecule inhibitors demonstrated promising antitumour response in malignant murine cells, thereby offering a potential anticancer tool for translating anti-CD73 therapeutic approaches to cancer patients.
Yang et al. Reference Yang, Du and Zu71 investigated CD73 expression in 106 prostate cancer tissue specimens, which were histologically confirmed as lymph node metastasizing (72 specimens) and non-metastasizing (34 specimens), using immunohistochemistry (IHC), qRT-PCR and Western blot. They reported CD73 expression in 94% of lymph node metastasizing samples and 9% of lymph node non-metastasizing samples, and that IHC, qRT-PCR and Western blot all demonstrated a positive association between CD73 expression and lymph node metastasis. They concluded that CD73 expression in lymph node metastasizing prostate cancer is significantly high compared with non-metastasizing disease, suggesting that CD73 has potential as a molecular therapeutic target for metastatic prostate cancer. Reference Yang, Du and Zu71 Leclerc et al. Reference Leclerc, Charlebois and Chouinard74 studied the prognostic value of CD73 protein expression in a tissue microarray composed of stromal and epithelial compartments from paired prostate cancer and normal adjacent tissues from 285 patient specimens. They reported that elevated levels of CD73 expression in the normal adjacent prostate epithelium is significantly associated with shorter biochemical recurrence-free survival. In contrast, high levels in tumour stroma are associated with longer biochemical recurrence-free survival and also negatively correlated with p65 expression in the nuclei of diseased cells. They concluded that CD73 is an independent prognostic factor and its expression in the stromal and epithelial compartments can potentially discriminate between aggressive and indolent forms of prostate cancer. Reference Leclerc, Charlebois and Chouinard74 Wang et al. Reference Wang, Tang and Wang72 studied whether CD73 promotes malignant phenotypes in carcinomas through inducing tumour angiogenesis by investigating its role in tumour angiogenesis using CD73 knockout and control mice. They observed larger tumour sizes in CD73+/+ mice than in CD73−/− mice, significantly higher formation of new capillaries in CD73+/+ pulmonary microvascular endothelial cells than in CD73−/− and reported that CD73 decreased endothelial cell adhesion to collagen IV and promoted migration. They concluded that CD73 promotes endothelial cells to form new capillaries, facilitate tumour angiogenesis, development and haematogenous metastasis and can potentially be targeted for inhibition of tumour angiogenesis and metastasis.
Lemur tyrosine kinase 2 (LMTK2)
The Lemur Tyrosine Kinases (LMTK) family are a structurally unique group of membrane-associated kinases composed of LMTK1, LMTK2 and LMTK3 and in recent years, the LMTK2 has become the focus of research when it was identified as a susceptibility gene for prostate cancer. Reference Manser, Guillot and Vagnoni75–Reference Shah and Bradbury77 The LMTKs are reported to be involved in cell proliferation, apoptosis, growth, differentiation, as well as cell migration which when turned awry can lead to cancer susceptibility. Reference Conti, Majorini and Fontanella78 The LMTK2 gene is located on the long arm of chromosome 7 at position 21.3 (7q21.3) and encodes a protein belonging to the kinase superfamily and the receptor tyrosine kinase (RTK) family. Reference Manser, Guillot and Vagnoni75–Reference Shah and Bradbury77,Reference Harries, Perry, McCullagh and Crundwell79–Reference Inoue, Kon and Ohkura82 A Genome-Wide Association Study (GWAS) of patients with prostate cancer identified rs6465657, which is a genetic variant of LMTK2, to be strongly associated with prostate cancer and thereby suggested that LMTK2 might be involved in the development and/or maintenance of prostate tumours. Reference Manser, Guillot and Vagnoni75–Reference Shah and Bradbury77 Several studies using in vitro models of prostate cancer have also shown LMTK2 to regulate the androgen receptor, PSA and vascular endothelial growth factor (VEGF) secretion and transforming growth factor beta (TGFβ) signalling, and could therefore contribute to cancer susceptibility and progression. Reference Manser, Guillot and Vagnoni75,Reference Shah and Bradbury77–Reference Harries, Perry, McCullagh and Crundwell79,Reference Chibalina, Seaman, Miller, Kendrick-Jones and Buss81,Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 According to Shah and Bradbury Reference Shah and Bradbury77 and Eeles et al., Reference Eeles, Kote-Jarai and Giles76 pharmacologic manipulation of LMTK2 activity could provide a novel therapeutic target for more effective treatment for patients with castrate-resistant prostate cancer.
Shah and Bradbury Reference Shah and Bradbury77 investigated LMTK2 expression and its role in modulating androgen receptor activity in normal prostate epithelial cells (PNT1A), androgen-sensitive prostate cancer cells (LNCaP) and metastatic prostate cancer cells (PC3). They reported that LMTK2 interacts directly with androgen receptors and negatively regulates its activity and that a decrease in LMTK2 protein expression is associated with an increase in androgen-mediated and androgen-independent activity of androgen receptors. Furthermore, they reported knockdown of LMTK2 protein in prostate cells significantly increases cell viability and tumourigenecity in the presence and absence of androgen, thus LMTK2 is a novel regulator of androgen receptors in prostate epithelium. They concluded that LMTK2 plays a role in the development of castrate-resistant prostate cancer and small molecules that enhance the activity of LMTK2 can decrease androgen receptors’ proliferative activity in prostate cancer patients, especially in patients with castrate-resistant prostate cancer. Reference Shah and Bradbury77 Harries et al. Reference Harries, Perry, McCullagh and Crundwell79 measured the expression and isoform usage of 7 genes identified by GWAS to be associated with prostate cancer by real-time PCR in 39 non-malignant BPH and 21 prostate adenocarcinoma specimens and further investigated their correlation with cancer status and genotype at the GWAS risk variants. They reported that the LMTK2 mRNA expression level in adenocarcinoma samples was 68% less than in non-malignant BPH samples. Furthermore, they reported that LMTK2 gene expression level is inversely correlated with the presence of prostate cancer and also correlated with the risk genotype at the GWAS variants rs6465657. They concluded that LMTK2 gene expression is altered in prostate cancer and is an important determinant in the disease development. Reference Harries, Perry, McCullagh and Crundwell79 Shui et al. Reference Shui, Lindström and Kibel84 investigated the relationship of 47 established prostate cancer risk single-nucleotide polymorphisms (SNPs), including the LMTK2 risk allele of rs6465657, with prostate cancer-specific mortality in a cohort of 10,487 men who had prostate cancer and 11,024 controls with a median follow-up time of 8·3 years, in which time 1,053 prostate cancer deaths occurred. They reported that the LMTK2 rs6465657 SNP has a risk allele that is inversely associated with prostate cancer-specific mortality and associated with nonfatal prostate cancer compared to controls.
Myosin VI (MYO6)
Myosins are a large multigene family of actin-based molecular motors with ATPase activity which are essential to eukaryotic homeostasis and are involved in growth and tissue formation, metabolism, reproduction, communication, reshaping and movement of cells in the body. Reference Inoue, Kon and Ohkura82,Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83,Reference Heissler, Sellers, Bradshaw and Stahl85–Reference Dunn, Chen and Faith87 According to Heissler and Sellers, Reference Heissler, Sellers, Bradshaw and Stahl85 there are 39 myosin genes in humans that are categorised into 13 members and, although the specific activities of the myosins differ, they all function as motor proteins. The myosin VI (MYO6) gene encodes a reverse-direction motor protein involved in intracellular vesicle and organelle transport, receptor-mediated endocytosis, migration and cell–cell interactions, as well as in the modulation of RNA polymerase II-dependent transcription. Reference Inoue, Kon and Ohkura82,Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83,Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86,Reference Dunn, Chen and Faith87 Chibalina et al. Reference Chibalina, Seaman, Miller, Kendrick-Jones and Buss81 and Puri et al. Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 reported that MYO6 interacts with the glucose transporter-binding protein GLUT1CBP (GIPC) and LMTK2 on early endosomes in the recycling pathway, which are the only binding partners that bind to MYO6. According to Puri et al., Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 since MYO6 is a multifunctional motor protein involved in different cellular pathways, it may potentially promote prostate carcinogenesis through a number of distinct mechanisms or pathways. Several studies have reported overexpression of the MYO6 gene in prostate cancer epithelium and the two precursors for prostate cancer (i.e., proliferative inflammatory atrophy and prostatic intraepithelial neoplasia) and that the overexpression has a positive correlation with the presence of androgen receptor in cell lines. Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83,Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86,Reference Dunn, Chen and Faith87 Additionally, Puri et al. Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 and Loikkanen et al. Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86 reported that inhibiting MYO6 expression reduces the motility of prostate cancer cells. According to Loikkanen et al., Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86 MYO6 plays a significant role in regulating androgen receptor gene expression and holds promise as a therapeutic target for regulating androgen receptor-dependent gene expression.
Puri et al. Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 investigated the role of MYO6 in prostate cancer development by characterising its intracellular localisation and function in the LNCaP prostate cancer cell line. They used light and electron microscopy to identify MYO6 on Rab5-positive early endosomes, recycling endosomes and the trans-Golgi network. They reported that MYO6 overexpression in LNCaP cells enhances secretion of PSA and VEGF, whereas downregulation of MYO6 expression by small interference RNA (siRNA)-mediated knockdown significantly reduces PSA and VEGF secretion. They suggested that MYO6 overexpression enhances prostate tumour growth and metastasis by increasing the secretion of growth factors and potential ECM proteases. Reference Puri, Chibalina, Arden, Kruppa, Kendrick-Jones and Buss83 Loikkanen et al. Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86 studied the effect of MYO6 downregulation in LNCaP human prostate cancer cell line using an RNA interference approach and the expression of MYO6 in human prostate tissue using archival prostate samples of 20 consecutive samples of prostatic needle biopsies and 32 acinar adenocarcinomas of different Gleason grades. They observed that MYO6 expression in human prostate cancer tissue is more highly expressed in malignant epithelium than benign epithelium, and MYO6 knock-down decreased expression of androgen receptors. They concluded that MYO6 is a modulator of androgen-dependent gene transcription via interaction with the androgen receptors and is a potential therapeutic target for prostate cancer as it could be used to modulate androgen receptor-dependent gene expression. Reference Loikkanen, Toljamo, Hirvikoski, Väisänen, Paavonen and Vaarala86 Dunn et al. Reference Dunn, Chen and Faith87 evaluated the expression of MYO6 in normal prostate epithelium and cancerous acini from 240 patients’ sample. They identified MYO6 as one of the top genes that demonstrated cancer-specific overexpression in clinical prostate specimens and observed the highest expression level in medium-grade androgen-dependent prostate cancers, whereas androgen-independent more advanced and aggressive cancers show significantly less overexpression. Furthermore, they reported that MYO6 protein expression in cell lines positively correlates with the presence of androgen receptors and siRNA-mediated MYO6 knockdown in LNCaP human prostate cancer cell line impaired cell migration. Reference Dunn, Chen and Faith87
Osteopontin (OPN)
Osteopontin (OPN) is a matricellular protein encoded by the OPN (or SPP1) gene located on the long arm of chromosome 4 at position 22.1 (4q22.1). The OPN protein mediates diverse physiological and pathophysiological processes such as cell adhesion, migration, invasion, proliferation, tissue remodelling, bone formation, early inflammatory responses, wound healing and angiogenesis. Reference Nakamura, Tilli and Wanderley88–Reference Weber92 According to Nakamura et al., Reference Nakamura, Tilli and Wanderley88 OPN is subject to alternative splicing which generates three isoforms (i.e., OPNa, OPNb and OPNc), and whereas OPNa corresponds to the full-length isoform, OPNb and OPNc lack exon 5 and exon 4, respectively. Furthermore, they reported that the PI3K signalling pathway mediates the role of either OPNb or OPNc in prostate cancer progression and cells overexpressing OPNb or OPNc proliferate more rapidly than cells overexpressing OPNa. Several studies have also reported that OPN is frequently overexpressed in human prostate cancer tissue, influences tumour growth and proliferation and facilitates the formation of bone metastases. Reference Nakamura, Tilli and Wanderley88–Reference Weber92 According to Aksoy et al., Reference Aksoy, Artas and Sevindik89 OPN plays an important role in metastasis and resistance to chemotherapeutics through activation of the PI3K/Akt pathway and its overexpression is a potential marker of proliferation and resistance to taxane-based regimen in metastatic castrate-resistant prostate cancer. Weber et al. Reference Weber, Lett and Haubein93,Reference Weber, Lett and Haubein94 reported that OPN expression is associated with tumour stage, grade and early tumour progression and is a predictor of disease-free and overall survival. Wisniewski et al. Reference Wisniewski, Winiecki, Makarewicz and Zekanowska91 also reported that plasma OPN levels are associated with disease progression and worse prognosis, and are an independent risk factor for biochemical recurrence after prostatectomy, and also that elevated OPN levels are a potential predictor of bone metastases in prostate cancer patients.
Aksoy et al. Reference Aksoy, Artas and Sevindik89 investigated OPN expression in biopsy specimens of 30 patients with metastatic castrate-resistant prostate cancer and evaluated the relationship between its expression levels and prediction of response to taxane-based regimen. They reported that OPN overexpression is significantly correlated with lower Gleason scores, may help identify patients with lower Gleason scores and is a potentially useful predictor of poor prognosis in patients with metastatic castrate-resistant prostate cancer. Reference Aksoy, Artas and Sevindik89 Yuanbing et al. Reference Yuanbing, Gan and Wang95 studied OPN expression in tissue samples from 100 prostate cancer patients to evaluate its correlation to the prognosis of disease recurrence and survival as well as with clinicopathological features. They reported that OPN positivity in prostate cancer tissue is correlated with Gleason score, tumour staging and bone metastasis and is a potential prognostic marker for survival in patients. Reference Yuanbing, Gan and Wang95 Forootan et al. Reference Forootan, Foster and Aachi90 analysed OPN expression levels in benign and malignant prostate epithelial cell lines and in an archival set of a large number of prostate tissues to determine if OPN expression can independently predict the aggressiveness of prostate cancer. They observed elevated levels of OPN in both malignant prostate cell lines and tissues compared with benign samples, and reported that OPN overexpression is significantly associated with increased malignant characteristics of carcinoma cells, Gleason score and reduced survival time of patients. They concluded that elevated OPN level is involved in malignant progression of prostate cancer and is a potentially useful prognostic factor to predict patients’ outcomes. Reference Forootan, Foster and Aachi90 Nakamura et al. Reference Nakamura, Tilli and Wanderley88 investigated the cellular mechanisms by which OPN splice variants mediate PC3 prostate cancer cell survival and growth in response to docetaxel-induced cell death. They reported that PC3 cells overexpressing OPNb or OPNc splice variants are highly resistant to docetaxel-induced cell death. They demonstrated that the EMT programme is one of the molecular mechanisms mediating the survival of PC3 cells overexpressing OPNb or OPNc in response to docetaxel treatment. Reference Nakamura, Tilli and Wanderley88
Prostate-specific membrane antigen (PSMA)
Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein with several enzymatic activities and it is encoded by the PSMA (or FOLH1, folate hydrolase 1) gene located on the short arm of chromosome 11 at position 11.12 (11p11.12). Reference Osei, Swanson and Francis11,Reference Nagaya, Nagata and Lu96–Reference Xiao, Adam and Cazares103 According to Bouchelouche et al., Reference Bouchelouche, Choyke and Capala97 PSMA is expressed in secretory cells within the prostatic epithelium and is absent or moderately expressed in hyperplastic and benign tissue. Xiao et al. Reference Xiao, Adam and Cazares103 reported that, since the discovery of PSMA, a variety of techniques such as tissue immunohistochemistry, reverse transcription PCR, in situ hybridisation and Western blot analysis have been used to demonstrate that it is expressed predominantly in prostate tissue, thus it is downregulated in BPH, but overexpressed in primary, metastatic prostate carcinoma and in patients with recurrences after androgen deprivation therapy. Several studies have reported that PSMA expression level increases with tumour aggressiveness, tumour stage, androgen-independence, metastatic disease, disease recurrence and Gleason score. Reference Nagaya, Nagata and Lu96,Reference Hupe, Philippi and Roth100,Reference Chang102,Reference Ross, Sheehan and Fisher104 According to Wüstemann et al., Reference Wüstemann, Haberkorn, Babich and Mier98 PSMA provides the possibility of developing new strategies for prostate cancer diagnosis and therapy since it is known to be highly overexpressed on malignant prostate tumour cells and its expression level also correlates with disease aggressiveness. Consequently, several studies are exploiting the specificity of PSMA to prostate cancer for diagnostic imaging strategies using anti-PSMA antibodies as well as its upregulation by androgen deprivation for anti-PSMA therapies for the treatment of hormone-refractory prostate cancer and metastatic disease. Reference Bouchelouche, Choyke and Capala97–Reference Chang102,Reference Ross, Sheehan and Fisher104
Ross et al. Reference Ross, Sheehan and Fisher104 investigated the role of PSMA expression status as a predictor of prostate cancer using formalin-fixed paraffin-embedded sections of 136 prostatectomy specimens. They observed elevated expression levels of PSMA in prostate cancer cells compared to benign cells and serum PSA level at diagnosis for PSMA-overexpressing tumours was significantly higher than serum PSA for non-PMSA-overexpressing cohorts. They reported that high PSMA expression correlates with tumour grade, pathological stage, aneuploidy and biochemical recurrence. Furthermore, PSMA protein overexpression in high-grade primary prostate tumours and metastatic lesions correlated with increased PSMA mRNA expression levels and that PSMA expression is an independent predictor of biochemical recurrence. They concluded that overexpression of PSMA in primary prostate cancer correlates with other adverse traditional prognostic factors and independently predicts disease outcome. Reference Ross, Sheehan and Fisher104 Hupe et al. Reference Hupe, Philippi and Roth100 assessed the prognostic value of PSMA expression as a potential PSMA-based risk stratification of prostate cancer patients with localised disease at the time of initial diagnosis on 294 preoperative biopsies, 621 primary tumour foci from 242 radical prostatectomy patients specimens, 43 locally advanced or recurrent tumours, 34 lymph node metastases, 78 distant metastases and 52 benign prostatic specimens. They correlated PSMA expression with clinicopathologic features such as recurrence-free survival, PSA serum level, TNM-stage and the International Society of Urologic Pathologists (ISUP)/World Health Organization (WHO) grade groups. They reported significantly elevated PSMA levels during prostate cancer progression and high PSMA on both preoperative biopsy and radical prostatectomy specimens is significantly associated with a higher risk of disease recurrence following curative surgery. Furthermore, they reported that high PSMA expression on biopsy specimens is significant in predicting increased risk of disease recurrence independently from established prognostic markers and that elevated PSMA expression on biopsy is strongly associated with low recurrence-free survival. They concluded that PSMA is an independent prognostic marker on biopsies at initial diagnosis and can predict disease recurrence following curative therapy and proposed the routine use of PSMA for outcome prediction and decision-making in risk-based prostate cancer management on biopsies at initial diagnosis. Reference Hupe, Philippi and Roth100
Conclusion
The concept of personalised and targeted medicine holds promise for prostate cancer patients and will depend on the identification of clinical biomarkers or a panel of biomarkers that could potentially account for individual patient variabilities and capable of interrogating key genetic aberrant pathways likely targetable with molecular targets or immunologic therapies. Emerging biomarkers have the potential to shift the treatment paradigm of prostate cancer towards more personalised medicine since they are capable of offering an improved understanding of the biology responsible for prostate carcinogenesis and progression, predicting disease and for patients with the established disease can assist in defining the nature of the disease, identifying patients with a greater likelihood of benefiting from specific treatment and monitoring the success of treatment. Furthermore, personalised medicine has the potential for patient-specific intervention based on patient-specific disease susceptibility, diagnostic or prognostic information or treatment selection for the optimum response thereby substantially impacting disease mortality, increasing patient survival and potentially reducing the rates of avoidable invasive treatments. Future research should focus on validation of already existing biomarkers and the discovery of new effective clinical biomarker panels capable of identification of patients with aggressive disease, screening for early disease detection and diagnosis, patient stratification at diagnosis into different risk categories, identification of patients’ risk for metastatic disease and subsequent relapse and real-time monitoring of patient response to a specific treatment.
Acknowledgements
The authors would like to acknowledge with much gratitude the financial support from the Kitchener–Waterloo Chapter of the TELUS Ride for Dad and the Prostate Cancer Fight Foundation for prostate cancer research at the Grand River Hospital.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
