Transmembrane Protease Serine 2 in Prostate Cancer: Comparison
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Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Alexandros Georgiou.

The abundant expression of TMPRSS2 is evident in normal prostatic tissue. Different endogenous substrates of TMRPSS2 have been identified, including the epithelial sodium channel (ENaC) the protease-activated receptor-2 (PAR-2), as well as other serine protease-like zymogens, such as kallikrein-2 (KLK2), suggesting its potential contribution to prostate homeostasis and its plausible involvement in male fertility. The TMPRSS2:ERG fusion is considered relevant to prostate cancer, but its association with the development and progression as well as its clinical significance have not been fully elucidated. 

  • TMPRSS2
  • androgen receptor
  • prostate cancer
  • Gleason score
  • Molecular pathology

1. Introduction

After lung cancer, prostate cancer is the second leading cause of cancer-related death in men, according to the latest data provided by Cancer Statistics 2022 [1]. There is a geographical variation in prostate cancer incidence. In developed countries, the disease is more prevalent than in developing countries. Various factors may contribute to these differences in incidence rates, including lifestyle, diet, genetics, and access to healthcare [2]. Researchers limited knowledge about the physical history of prostate cancer, as well as the unmapped molecular events occurring before and after hormone treatment, limits the therapeutic options. In the past few years, advances in molecular biology and the widespread use of sequencing techniques in medical research have transformed researchers understanding of this disease, paving the way to precision medicine [3,4][3][4].
There is evidence that androgen receptor (AR) co-activators are implicated in both androgen-dependent and androgen-independent prostate cancer [5,6][5][6]. The pathogenetic role of the AR pathway is evident in the majority of prostate cancer cases, both androgen-dependent and castration-resistant, as indicated by the continuously increasing levels of the prostate-specific antigen (PSA). Molecular studies of AR co-activators have been widely conducted to understand prostate cancer progression. There are some co-activators that play a tumor suppressor role, while others play a positive role in regulating cancer progression [7,8][7][8].

2. Biological and Biochemical Features of TMPRSS2

2.1. Biological and Biochemical Features of TMPRSS2

The transmembrane protease serine 2 (TMPRSS2) is a member of the type II transmembrane serine protease (TTSP) family. The TMPRSS2 gene is located on chromosome 21q22.3, and it is expressed in different anatomic locations in a time-preset manner, including in the fetal nervous system and the adult respiratory epithelium [9,10][9][10]. High expression is also marked in the prostate epithelial cells. The TMPRRS2 gene harbors androgen-responsive elements in the 5′-UTR regions, placing its expression under hormonal control through the stimulation of the AR [9,11][9][11].
The advent of the COVID-19 pandemic brought TMPRSS2 into the spotlight of the scientific community due to its significant function in facilitating the entry of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its variants into the host cells [12,13,14][12][13][14]. These scientific investigations have not only illuminated the comprehension of the pathogenic mechanisms of the virus that allow cell entrance, but they have also unraveled the molecular structure and certain biological functions of TMPRSS2. As a member of the TTSP family, TMPRSS2 is produced as a zymogen and undergoes post-transcriptional modifications to obtain its active structure. TMPRSS2 consists of three distinct regions, including an intracellular portion, a transmembrane domain, and an extracellular domain. The latter harbors the proteolytic function of the molecule, and it is in part highly conserved among TTSPs [15].
Two different isoforms of the TMPRSS2 protein, occurring through alternative splicing of mRNA, have been identified. Both isoforms share similar transmembrane and extracellular domains. Isoform 1 exhibits a longer N-terminal intracellular domain and contains 32 more amino acids than isoform 2. They are produced as zymogens, and they are autocatalytically activated [9,16][9][16]. The extension in isoform 1 is thought not to affect its efficiency in autocatalytic activation; however, it might influence cleavage specificity [16].

2.2. The Biological Role of TMPRSS2 in the Normal Prostate Gland

Although the abundant expression of TMPRSS2 is evident in normal prostatic tissue, its exact biological role is not clear. Different endogenous substrates of TMRPSS2 have been identified, including the epithelial sodium channel (ENaC) [17] the protease-activated receptor-2 (PAR-2) [18], as well as other serine protease-like zymogens, such as kallikrein-2 (KLK2) [19], suggesting its potential contribution to prostate homeostasis and its plausible involvement in male fertility. On the other hand, Kim et al. observed no phenotypic alterations resulting from the loss of TMPRSS2 expression in their study in murine animal models. By using homologous recombination, they disturbed the serine protease domain, generating Tmprss2−/− knockout mice. Compared to their wild-type counterparts, the Tmprss2−/− mice showed no phenotypic difference in terms of survival, normal prostatic development, and growth or fertility. Based on this finding, they suggested the presence of functional redundancy with other members of the TTSP family or the fact that the TMPRSS2 specialized role is evident under stressful situations or diseases [20].

2.3. The Role of TMPRSS2 in Prostate Carcinogenesis

TMPRSS2 is dysregulated in several types of malignant neoplasms, including breast, lung, gastric, ovarian, and renal carcinomas. There are diverse expression patterns within distinct tumor subtypes, as well as in comparison to the adjacent normal tissue parenchymal. In addition, there is a positive correlation between increased TMPRSS2 expression and the levels of immune infiltrates in breast cancer and lung adenocarcinoma [21]. Conversely, in a different study, TMPRSS2:ERG fusion detected by RNA sequencing in prostate cancer samples was associated with a lower lymphocytic infiltration, a finding that could potentially interfere with the biology of the tumor immune response [22]. The extent of immune cell infiltration in tumors is known to serve as a prognostic factor for survival [23,24][23][24]. As such, TMPRSS2 may serve as an important biomarker for the prognosis of patients with cancer.
The enzymatic activity of TMPRSS2 has also been implicated in cancer invasion. Ko et al. performed in vitro studies in three different prostate cancer cell lines: NCaP, PC3, and DU145. TMPRSS2 overexpression in these three cell lines had no effect on cell growth, but it was significantly associated with increased invasiveness. The latter is believed to be associated with the proteolytic activity of TMPRSS2, as DU145 cells transduced with a mutant version of TMPRSS2 with impacted protease activity did not demonstrate increased cellular motility [25]. Another study used the transgenic adenocarcinoma of the mouse prostate (TRAMP) model and found that TMPRSS2 expression was correlated with an increased frequency of gross metastasis. Additionally, the study suggested that TMPRSS2 plays a critical role in the enzymatic activation of the hepatic growth factor (HGF), which, in turn, promotes c-MET receptor tyrosine kinase signaling, leading to the enhancement of a pro-invasive epithelial-to-mesenchymal transition phenotype [19]. Moreover, in a study conducted by Wilson et al., TMPRSS2 was found to be able to catalytically activate PAR-2 in prostate cancer cell lines, leading to the increased expression of matrix metalloproteinases 2 and 9. These two molecules are known to degrade the extracellular matrix, enhancing cancer metastasis [18].
Another important aspect of the pathogenetic role of TMPRSS2 in cancer is its involvement in chromosomal rearrangements. Chromosomal rearrangements were known to participate in the development of hematological malignancies and sarcomas, but their association with the pathogenesis of common solid carcinomas was largely unexplored. In a study performed by Tomlins et al., a recurrent chromosomal rearrangement between the TMPRSS2 gene and two members of the E26 transformation-specific (ETS) family of transcription factors, namely the ETS-related gene (ERG) and ETS variant transcription factor 1 (ETV1), was identified. These molecules were previously found to be overexpressed in prostate cancer, and their aberrant expression was linked to the occurrence of this genomic event [26]. Subsequent inquiries revealed that other members of the ETS family, such as ETV4, can also participate in molecular fusion with the TMPRSS2, albeit with a lesser frequency. Collectively, these findings imply that the overexpression of the ETS transcription factors, resulting from chromosomal rearrangements involving the TMPRSS2 genetic elements, represents a crucial facet of the molecular pathology of prostate cancer [27].
The fusion of the promoter of TMPRSS2 with the coding region of ERG is the most prevalent molecular aberration in prostate cancer; it occurs in approximately 50% of prostate cancer cases and is the most common gene fusion in solid tumors [28]. Both genes are located on chromosome 21, about 3Mb apart. The fusion is considered to occur early in the pathogenesis of prostate cancer and can be caused by either genomic translocation or interstitial deletion of the intergenic region between the two genes. The promoter region of the TMPRSS2 contains androgen-sensitive elements, and as a result, this fusion sets the expression of ERG under hormonal control, promoting its overexpression in the settings of an androgen-rich environment [29,30,31][29][30][31].
Several studies tried to investigate the pathogenetic role of TMPRSS2:ERG fusion in carcinogenesis and the development of prostate cancer. Zhou et al. demonstrated that ERG promotes the expression of the α1 and β1 subunits of soluble guanylyl cyclase (sGC), which catalyzes the production of cyclic guanosine monophosphate (cGMP) in endothelial cells. The study highlights the fact that TMPRSS2:ERG fusion transcriptionally upregulates sGC; promoting cGMP synthesis in prostate cancer cells thus enhances cellular proliferation. The pro-proliferative activity of the sGC-cGMP pathway is potentially linked to the activation of PI3K/AKT signaling, which is a downstream target of the sGC-cGMP pathway, modulating cell survival, migration, and angiogenesis [32].
Deplus et al. developed cell lines of luciferase-expressing PC3M cells carrying the TMPRSS2:ERG fusion. In vitro analysis showed increased migration rates of cells carrying the fusion compared to control cells. In the same study, the researchers injected these two cell lines into murine models. They observed that the mice injected with the TMPRSS2:ERG positive cells showed a 57% higher incidence of bone metastasis. Interestingly, these metastases were predominantly located in the hind limbs and spine, which are the two most common anatomical sites affected by prostate cancer in humans. In addition, the authors conducted transcriptomic profiling to investigate the differences in gene expression between the fusion-positive and control cell lines. According to the results of this study, the overexpression of TMPRSS2:ERG was associated with the aberrant expression of the genes that enhance osteomimicry of cancer cells, facilitating their invasion and growth in bone tissue [33].

3. Clinical Implications of TMPRSS2:ERG Fusion in Prostate Cancer

Despite the fact that TMPRSS2:ERG fusion is a frequently occurring molecular event in prostate cancer, its precise impact on the clinical aspects of the disease remains controversial. Taris et al. investigated ERG expression throughout all stages of prostate cancer natural history, from high-grade prostatic intraepithelial neoplasia (HGPIN) to metastasis, in a multinational patient cohort. They observed that among Caucasian patients, ERG expression followed a positive trend from HGPIN (17.5%) to clinically localized prostate cancer (33%) and metastases (53%) (p = 0.01). Additionally, a higher level of ERG expression was correlated with a more advanced pathologic stage for tumors confined within the prostate gland (pT3 = 43%, pT2 = 27.5%). The authors also aimed to examine the prognostic importance of ERG expression in patients with prostate cancer who underwent surgical prostatectomy. They utilized a case–control population of 65 patients with recurrence and 65 patients without recurrence. Following adjustments for age, preoperative PSA, Gleason score, and pTNM stage, the study found a significant correlation between ERG expression and biochemical progression-free survival. This so-called “prognostic-paradox” regarding the correlation of TMPRSS2:ERG fusion with a more advanced disease and a more favorable prognosis may be attributed, at least in part, to the fact that the expression of ERG is dependent on the AR activation, indicating a potential for an improved response to hormone castration interventions [34]. Chalmers et al. sought to investigate the molecular aberrations that define early-onset prostate cancer, as a distinct and understudied clinical entity. Patients with early-onset prostate cancer exhibit a lower frequency of risk factors and are likely to possess multiple genetic mutations that dictate a more aggressive disease phenotype. The study analyzed comprehensive genomic profiling data from 10,189 prostate cancer patients of different racial and age groups. Interestingly, the incidence of TMPRSS2 fusions was higher in patients aged ≤50 years than those aged ≥60 years, with a decreasing incidence with age, while other gene alterations tended to increase with age. The findings of this study suggest that a distinct group of young patients with aggressive prostate cancer is frequently associated with TMPRSS2:ERG fusions, while exhibiting a lower likelihood of harboring mutations in other genes, such as AR, SPOP, and ASXL1 [35]. The detection of the TMPRSS2:ERG fusion gene in urine samples after digital rectal examination as a non-invasive procedure was studied over a decade ago. The results since then have been quite encouraging as the urine test featured, despite its low sensitivity of 37%, a specificity of 93% and a positive predictive value of 94% in post-DRE urine samples examined from men with PCa-positive and PCa-negative biopsies using semiquantitative reverse transcription PCR (RT -PCR). Indeed, when the detection of TMPRSS2:ERG fusion was combined with PCA3 RNA transcripts, the sensitivity of the method was improved. Therefore, the combination could be used as a diagnostic marker in patients with indications of prostate cancer, such as elevated serum PSA values and a history of negative biopsy, directing the need for a repeat biopsy [36,37][36][37]. A few years ago, a meta-analysis demonstrated that ERG overexpression or positive fusion status was associated with the advanced pathological characteristics of patients with prostate cancer. More specifically, TMPRSS2:ERG fusion was more common in the T3–4 stages of PCa than in the T1–2 stages and in cases with distant metastasis (M1), whereas no difference was observed in the lymph node status. Moreover, the fusion gene was common in young patients aged ≤65, in patients with high PSA levels (>10 ng/mL), and in cases with peripheral involvement. The TMPRSS2:ERG fusion was not associated with biochemical recurrence [38]. Regarding the association with the Gleason score in the meta-analysis of Song et al., as well as that of Fine et al., the TMPRSS2:ERG fusion was more frequently associated with the lower scores (≤7) and was associated with less aggressive histological features of prostate cancer [38,39][38][39]. The association of ERG overexpression with specific histomorphologic features and prognosis in prostate cancer has been a topic of debate since the discovery of the TMPRSS2:ERG fusion. However, studies conducted worldwide have reported conflicting findings. Fine et al. conducted FISH analysis in a cohort of prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy study to investigate the correlation between TMPRSS2:ERG fusion and the Gleason score. The study revealed that the genomic rearrangements in TMPRSS2:ERG were associated with a lower Gleason score, while an increase in gene copy number was linked to a higher Gleason score [39]. In another study, conducted by Peterson et al., the expression of ERG protein, serving as an indicator of TMPRSS2:ERG gene fusion, was evaluated using immunohistochemical staining in a cohort of 1180 patients. In the same inquiry, the authors performed a meta-analysis of 47 studies to further investigate the association between gene rearrangement and the prognosis of the patients. The study revealed that 49% of the cohort exhibited ERG overexpression and that they were more likely to have a higher tumor stage; however, no significant correlation was observed between the ERG expression and the Gleason score or the clinical outcomes of the disease. These findings were supported by the concurrent meta-analysis, which revealed that the presence of TMPRSS2:ERG fusion increased the risk of a higher tumor stage at diagnosis but did not correlate with the final outcome [40]. Overall, TMPRSS2:ERG fusion is considered to be relevant for the disease. However, its correlation to prostate cancer development and progression, as well as its clinical significance, are not yet fully clarified. Due to its high frequency in prostate cancer cases, the TMPRSS2:ERG fusion might be more promising as a diagnostic marker rather than as prognostic [41]. Taxanes remain up to date in the main chemotherapeutic regimen in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, in preclinical studies the TMPRSS2:ERG rearrangement has been associated with taxane resistance. Reig et al. evaluated TMPRSS2:ERG expression in peripheral blood mononuclear cells and tumor tissue from mCPRC patients treated with taxanes. The results of this study indicate that the detection of TMPRSS2:ERG in blood from mCRPC patients treated with docetaxel is correlated with lower PSA response rate (12.5% vs. 68.3%, p = 0.005), as well as clinical/radiological-PFS (3.1 mo vs. 8.2 mo, p < 0.001) [42]. In an effort to evaluate the prognostic value of TMPRSS2:ERG in patients with mCRPC treated with enzalutamide, an early phase clinical trial described better PSA responses in TMPRSS2:ERG-associated tumors. However, the latest clinical trial phase II proved that the fusion has limited value as a predictive biomarker in mCRPC treated with anti-androgen therapies, such as abiraterone [43].

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