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Figiel, S.; Cancel-Tassin, G.; Mills, I.G.; Lamb, A.D.; Fromont, G.; Cussenot, O. Molecular Anatomy of the Prostate. Encyclopedia. Available online: https://encyclopedia.pub/entry/50841 (accessed on 01 July 2024).
Figiel S, Cancel-Tassin G, Mills IG, Lamb AD, Fromont G, Cussenot O. Molecular Anatomy of the Prostate. Encyclopedia. Available at: https://encyclopedia.pub/entry/50841. Accessed July 01, 2024.
Figiel, Sandy, Géraldine Cancel-Tassin, Ian G. Mills, Alastair D. Lamb, Gaelle Fromont, Olivier Cussenot. "Molecular Anatomy of the Prostate" Encyclopedia, https://encyclopedia.pub/entry/50841 (accessed July 01, 2024).
Figiel, S., Cancel-Tassin, G., Mills, I.G., Lamb, A.D., Fromont, G., & Cussenot, O. (2023, October 26). Molecular Anatomy of the Prostate. In Encyclopedia. https://encyclopedia.pub/entry/50841
Figiel, Sandy, et al. "Molecular Anatomy of the Prostate." Encyclopedia. Web. 26 October, 2023.
Molecular Anatomy of the Prostate
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This entry is adapted from the peer-reviewed paper 10.3390/anatomia2040027

Understanding prostate carcinogenesis is crucial not only for identifying new treatment targets but also for developing effective strategies to manage the asymptomatic form of the disease. There is a lack of consensus about predicting the indolent form of the disease prostate cancer, leading to uncertainties regarding treatment initiation.

prostate cancer molecular anatomy histology genomic

1. Gene Expression According to Cell Types

The functional unit of the prostate gland is the acinar which comprises distinct layers of epithelial cells, each characterised by specific gene expression and functions [1].
The basal layer plays a crucial role in ensuring structural support and tissue integrity. It consists of basal cells that express cytokeratin (CK5, CK14), integrin α2β1, CD44, and TP63 genes, while lacking AR expression [1][2][3][4][5]. These basal epithelial cells also express genes associated with castration resistance, such as BCARC1 (p130cas) and EGFR [6][7], and with angiogenesis, such as NRP1 and VEGFA [8]. Of note, rare neuroendocrine cells are found within this layer, exhibiting positive staining for Chromogranin A and other neuropeptides [9]. These cells have a developmental stem cell of origin in common with epithelial cells [10]. The basal stem cells are responsible for the development and renewal of differentiated and functional luminal cells in adult prostatic glands [11][12]. The luminal cells, in direct contact with the basal cells, secrete substances like prostate-specific antigen (KLK3/PSA) and other kallikreins contributing to the secretion of the seminal fluid. These cells express the AR along with a combination of AR pathway drivers such as FOXA1 and HOXB13, as well as AR-targeted genes such as KLK3, KLK2, TMPRSS2, PSMA, and PSCA [13][14].
Additionally, there is a population of transit amplifying cells that may encompass ‘Club’ (KRT4+, SCGB1A1+) and “hillock” (KRT13+) cells described by G.H. Henry et al. [15][16]. In a normal adult prostate, these cells are rare; they are more frequent in foetal prostates and in pre-tumoral conditions [17]. These cells are characterised by the co-expression of basal and luminal cytokeratin, high proliferation, and a lack of the cyclin-dependent kinase inhibitor p27 (CDKN1B). This gene is involved in cell cycle arrest, wherein increased level of p27 indicates an exit from the cell cycle [18]. In adult prostatic glands, p27 is expressed by all cells in the luminal compartment and by a subpopulation of basal cells. Conversely, p27 downregulation occurs not only in most prostate cancers [19] but also in high grade prostatic intraepithelial neoplasia (PIN) [20].
Positioned beneath the basal layer and separated by a basement membrane [21], the non-epithelial prostate microenvironment, collectively termed ‘stroma’, is composed of various cell types. The stroma is a complex cellular network that plays a vital role for normal prostate development and related diseases [22][23][24][25].
The predominant cell type within the stroma is fibroblasts, which when beside cancer can be known as cancer-associated fibroblasts (CAF). CAFs can be identified by specific markers such as vimentin, ZEB1, MMP2, COL1A1, COL1A2, ASPN, BGN, and SFRP4 [22][26][27]. Smooth muscle cells are also present in the stroma and can be distinguished by the expression of ACTA2, MYLK, CALD1, and CNN1 [28][29]. In prostate cancer, the reactive stroma is characterised by a higher proportion of fibroblasts/myofibroblasts, which is offset by a decrease in differentiated smooth muscle cells [30][31][32].
Apart from fibroblasts and smooth muscle cells, the stroma contains other components, including blood vessels, lined by endothelial cells expressing endothelial receptors (EDNR and CD31) [33][34]. The stroma also houses nerves and a diverse infiltration of inflammatory immune cells, T cell phenotypes (CD3, CD45), macrophage phenotypes (CD68), granulocytes (CD24, CD15), and B cells (CD19, CD20) [35][36].
Altogether, epithelial layers and stroma form a complex and dynamic network, wherein effective bidirectional communication between prostate epithelial cells and the stroma is crucial for prostate development, renewal, and secretory function [37][38]. The secretion of growth factors, such as transforming growth factor beta (TGFβ) and fibroblast growth factors (FGF), are key players ensuring these functions and efficient communication [39][40]. Indeed, stroma cells secrete FGF7 and FGF10, primarily affecting epithelial cells and lead to the development of prostate cancer by increasing sensitivity to androgens [41][42][43][44][45]. Conversely, epithelial cells secrete FGF2, which regulates fundamental stromal processes such as angiogenesis and cell proliferation [46]. In addition, TGFβ is an important mediator of bidirectional communication, promoting tumour growth and metastasis by facilitating epithelial-to-mesenchymal transition in epithelial cells [47][48]. TGFβ-secreting epithelial cells influence stromal cell behaviour, including proliferation and extracellular matrix production, thereby supporting tumour invasion and metastasis [49][50].
Stromal and epithelial prostate cells collaborate in the metabolism of sexual steroid hormones and fatty acids. Prostate tissue can locally synthesise dihydrotestosterone (DHT), the most potent androgen, from various androgen precursor molecules [51]. As a result, despite androgen deprivation, levels of these hormones in the prostate remain high enough to promote cancer progression [52]. This phenomenon led to the development of new anti-androgen drugs which target the enzymes involved in steroid synthesis or which directly target the AR in prostate cells. Additionally, it is well-established that fatty acid metabolism is a potential target of the epithelial-mesenchymal transition, a key driver of prostate cancer development [53][54]. Prostate cells undergo a shift in lipid beta-oxidation pathways during carcinogenesis, accompanied by increased expression of AMACR, ACLY, ACACA, and FASN enzymes involved in the lipid metabolism [55].

2. Impact of Genetic Susceptibility in Prostate Cancer

Polygenic susceptibility to prostate cancer is influenced by functional polymorphisms of a single nucleotide. These polymorphisms play crucial roles during prostate development and homeostasis, influencing the expression of specific prostate transcripts and carrying implications for prostate cancer risk [56] or fertility. In addition to rare germline mutations, which encompass DNA repair genes associated with prostate cancer susceptibility, these polymorphisms affect key pathways, including those related to the AR (HOXB13, FOXA1) and proliferation (MYC, FGF10) [56]. These genetic variations have been found to correlate with disparities in prostate cancer risk based on ancestral backgrounds.

3. Gene Expression According to Prostate Cancer Histopathological Features

Histopathological evaluation of prostate cancer involves the assessment of several key features, including the Gleason score, tumour grade, tumour stage, and the presence of extraprostatic extension [57][58]. Since 1996 [59], the Gleason score has been a widely used grading system that assesses the architectural patterns of cancer cells. The initial scoring system ranged from 2 to 10, where higher scores indicated a more aggressive disease. However, the scoring system has been revised to now range from 6 to 10 and is transposed into the International Society of Urological Pathology (ISUP) grading system, which ranges from 1 to 5 [60]. Tumour grade refers to the degree of cellular differentiation and is categorised as low grade (Gleason score 6 or ISUP-1), intermediate grade (Gleason score 7 (3 + 4) or ISUP-2 and Gleason score 7 (4 + 3) or ISUP-3), or high grade (Gleason score 8–10 or ISUP-4-5). Tumour stage provides information about the extent of cancer spread beyond the prostate gland and extraprostatic extension indicates the presence of cancer cells outside the prostatic edge.
Prostate cancer primarily consists of adenocarcinoma, but rare variants, comprising less than 5% of cases, have been identified [61][62][63]. These variants include acinar subtypes (such as cribriform, intraductal, mucinous, prostatic intraepithelial neoplasia-like carcinoma, signet ring cell carcinoma, sarcomatoid carcinoma, and pleomorphic giant cell carcinoma) and non-acinar subtypes (such as ductal carcinoma, carcinoma with neuroendocrine differentiation as small cell carcinoma, squamous cell carcinoma, and adenoid cystic carcinoma). Each variant has distinct histological and clinical features, leading to different outcomes. For instance, the mucinous variant tends to have a more favourable prognosis, with an approximately 80% 10-year survival rate, while the neuroendocrine variant has a poorer prognosis, with less than 10% survival at 10 years [9].
Typical acinar adenocarcinoma is characterised by glandular structures with a luminal phenotype, lacking basal cells and basement membrane layers. The diagnosis of typical acinar adenocarcinoma is confirmed in pathological practice by identifying AMARC+/P63- gland pattern using immunohistochemistry [64]. New tissue markers associated with prostate cancer, such as PCA3, DLX1, and HOXB6, as well as hypermethylated genes like GSTP1, APC, RASSF1, and copy number variations, have been identified and used in the development of new diagnostic tests based on molecular changes in prostatic secretions collected in the urine [65][66][67][68]. However, it is important to note that typical prostatic adenocarcinoma exhibits molecular heterogeneity [69][70][71]. In addition, gene expression profiling studies have identified distinct molecular subtypes of prostate cancer, including acinar and non-acinar subtypes [61][72][73]. The acinar subtype, characterised by glandular structures resembling normal prostate tissue, is the most common. In contrast, the non-acinar subtype lacks typical glandular structures and is often associated with more aggressive disease behaviour, higher Gleason scores, and poorer clinical outcomes compared to the acinar subtype [74].
Recent advances in genomic profiling have further subdivided primary prostate cancers into subgroups based on their genetic and epigenetic profiles [75][76][77][78][79]. The main subgroup consists of erythroblast transformation-specific (ETS) fusion-positive tumours (59%), resulting from a fusion between androgen-driven genes (TMPRSS2, SLC45A3) and embryogenic/oncogenic genes (ERG, ETV1/4, FLI1) [80][81]. These fusion-positive tumours, in particular TMPRSS2-ERG fusion-positive tumours (46%), often exhibit PTEN deletion and demonstrate upregulation of HDAC1 which is involved in the regulation of the AR. These tumours also show upregulation of NPY and PLA2G7, which are involved in cell growth, migration and invasion, along with downregulation of AZGP1, known to play a role in lipid metabolism [82][83][84][85]. Although these fusions are predominantly associated with the common acinar adenocarcinoma, they have also been detected in rare variants [86]. Interestingly, in prostate cancer, harbouring androgen dependent fusion genes, such as TMPRSS2-ERG, the AR switches from an antiproliferative to an oncogenic gene [80].
Other genetic alterations have been observed in adenocarcinoma, such as PTEN, AR, and SPOP [87][88]. PTEN plays a crucial role in regulating the phosphatidylinositol 3-kinase kinase (PI3K)- protein kinase B (AKT) signalling pathway, which controls cell growth, survival, and metabolism. PTEN is also known as a tumour suppressor gene in prostate cancer, and its loss or inactivation is associated with patterns of increased tumour aggressiveness in localised prostate cancer [89][90]. AR is a critical driver of prostate cancer, playing a key role in the growth and survival of cancer cells. Alterations in AR signalling, such as AR amplification, mutations, or ligand-independent activation, are frequently observed. Constitutively active variant ARs are also found in prostate cancer [91][92][93]. SPOP is an E3 ubiquitin ligase with mutations accounting for 11% of cases, which affect protein degradation and influence the development of adenocarcinoma [75]. Additional genetic alterations include FOXA1 and IDH1 mutations, found in 3% and 1% of cases, respectively [75].
Similar to acinar adenocarcinoma, rare variants of prostate cancer involve several genes in their development and progression. TP53 mutations are commonly found in small cell carcinoma of the prostate, contributing to its aggressive nature [71][94]. Cribriform patterns can be further classified based on the proportion of cancer cells exhibiting PTEN-loss and PD-L1 overexpression [95]. Genes such as AR, ERG, FOXA1/2, MUC16, RB1, CDH1, BRCA2, and TP53 have also been involved in different variants of prostate cancer [96][97][98].

4. Gene Expression Associated with Prostate Cancer Outcomes

Nowadays, histopathological patterns are well recognised to play a crucial role in determining the management approach for early-stage prostate cancer [99]. However, certain patterns such as large cribriform or intraductal patterns are not recommended for active surveillance due to their association with a higher risk of disease progression [100][101][102]. Rare events like BRCA2 germline mutations, which are known to have a worse prognosis, also exclude patients from active surveillance management [103]. The management approach of prostate cancer is complex, as exemplified by TMPRSS2-ERG, a key player in the initial development of prostate cancer [104], which is not correlated with the progression of the disease to its life-threatening stage. Conversely, molecular events linked to BRCA2, TP53, RB1, and AR become more frequent as prostate cancer progresses from the metastatic stage to the castration-resistant stage, indicating their involvement in the later stages of the disease [105].
Recently, genomic profiling has emerged as a valuable tool in prostate cancer prognosis and therapeutic decision-making, which may help to decipher the progression of prostate cancer [106][107]. It provides a molecular dimension that complements the traditional histopathological classification. Genomic prognostic signatures based on transcriptomic profiles have been developed to provide clinicians and patients with more confidence in selecting between active surveillance or radical therapies in the early stages of the disease [108]. These genetic signatures encompass biological processes that may play a central role in tumour initiation and progression. For example, the Prolaris® test [109][110] focuses on genes associated with proliferation, providing insights into the tumour’s growth rate. On the other hand, tests like OncotypeDx® [111][112] or Prostadiag® [87] incorporate multifunctional gene patterns, including proliferation, differentiation, androgen responsiveness, epithelial-mesenchymal transition, and the presence of cancer-associated fibroblasts, to provide a more comprehensive assessment of the tumour’s behaviour. In particular, the Prostadiag® signature has been extensively studied [87], wherein three distinct subgroups of tumours based on gene expression patterns have been found. The first subgroup (S1) comprises aggressive tumours (TMPRSS2-ERG+) often characterised by PTEN deletion or TP53 deficiency, indicating a higher risk of disease progression. The second subgroup (S2) consists of tumours (TMPRSS2-ERG+) with a low risk of progression, with a likelihood of less than 10%.

5. Gene Expression According to Key Prostate Cancer Signalling Pathways

One of the key signalling pathways involved in prostate cancer is the AR pathway [113][114][115]. The AR is a transcription factor playing a fundamental role in regulating gene transcription upon binding to androgens. Its activity involves intricate interactions with other transcription factors, nuclear translocation, and binding to response elements, resulting in both genomic and non-genomic activities [116]. In the context of prostate cancer, the dysregulation of the AR signalling pathway leads to increased AR activity and the expression of genes that promote tumour growth [113][114][115]. These modifications arise from various mechanisms, including amplification or mutations in the AR gene, alterations in co-regulatory proteins, and abnormal activation of downstream signalling molecules.
The AR protein is predominantly expressed in the luminal epithelial cells of the prostate [117]. In the luminal layer, the AR pathway maintains differentiation and secretion functions and blocks the cell cycle [118]. Ligand binding induces conformational changes that liberate the AR from heat shock proteins and expose its ligand-binding domain, which contains a nuclear localization signal [119][120]. The ligand-bound AR subsequently forms dimers and undergoes phosphorylation, which are translocated to the nucleus. Within the nucleus, the AR binds to specific elements of the androgen response on DNA and recruits coregulators or coactivators such as FOXA1, GATA2, NKX3-1, and HOXB13 [121][122][123][124][125]. In consequence, the transcription of targeted genes (such as KLK2, KLK3, TMPRSS2, CAMKK2, CDH2, SCL43A1, and FKBP5), playing pivotal roles in various biological functions such as tumour progression, cell cycle regulation, glycosylation, calcium metabolism, and lipid metabolism, is enhanced [124][125][126][127]. AR can also interact with other proteins, such as HES6 and E2F1 [128], during castration resistant conditions, and can also repress gene expression. In fact, by collaborating with EZH2-mediated repressive chromatin remodelling, the AR facilitates the repression of target genes [129].
The WNT/β-catenin pathway also plays an essential role in prostate cancer, influencing cell proliferation, invasion, and stem cell-like properties [130][131]. Although WNT-1 is generally found in low levels in primary prostate epithelial cells, its upregulation has been observed in lymph nodes and bone metastases [132]. Disruption of this pathway can result from genetic mutations or altered expression of key components, including β-catenin or APC. Mutations in APC and CTNNB1 have been identified in up to 22% of castration-resistant prostate cancers [133][134]. Interestingly, stromal cells release WNT proteins that can activate the WNT signalling pathway in tumour cells [130][135][136][137]. An important downstream target of this pathway is FOXA2, whose induction is essential for bone metastasis development in prostate cancer [138].
The PI3K/AKT/mammalian target of rapamycin (mTOR) leads to the increased expression of genes involved in cell proliferation, survival, and metabolism. Furthermore, it contributes to the development of resistance to androgen deprivation therapy [139]. Dysregulation of the PI3K/AKT/mTOR pathway is frequently observed in prostate cancer, with up to 42% of primary tumours and 100% of metastatic samples showing abnormalities in this pathway [105][133][134][140][141].
The RAS/mitogen activated protein kinase (MAPK) cascade transduces extracellular growth signals through transmembrane receptors to regulate gene expression and cellular functions [142][143]. It is frequently deregulated in cancer, including prostate cancer. The cascade involves activation of RAS and the rapidly accelerated fibrosarcoma (RAF)/ mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signalling pathway, leading to transcription of target genes such as MYC and cFOS.
Feedback loops and interactions between components enable cross-regulation within the cascades. A complex interplay unfolds between the PI3K/AKT/mTOR pathway and other oncogenic signalling cascades, including AR, MAPK, and WNT pathways, which further promotes the growth of prostate cancer and contribute to drug resistance [139][144]. These pathways interact and regulate each other.

References

  1. Toivanen, R.; Shen, M.M. Prostate Organogenesis: Tissue Induction, Hormonal Regulation and Cell Type Specification. Development 2017, 144, 1382–1398.
  2. Jaworska, D.; Król, W.; Szliszka, E. Prostate Cancer Stem Cells: Research Advances. Int. J. Mol. Sci. 2015, 16, 27433–27449.
  3. Prajapati, A.; Gupta, S.; Mistry, B.; Gupta, S. Prostate Stem Cells in the Development of Benign Prostate Hyperplasia and Prostate Cancer: Emerging Role and Concepts. Biomed. Res. Int. 2013, 2013, 107954.
  4. Cussenot, O.; Berthon, P.; Cochand-Priollet, B.; Maitland, N.J.; Le Duc, A. Immunocytochemical Comparison of Cultured Normal Epithelial Prostatic Cells with Prostatic Tissue Sections. Exp. Cell Res. 1994, 214, 83–92.
  5. Murant, S.; Handley, J.; Stower, M.; Reid, N.; Cussenot, O.; Maitland, N. Co-Ordinated Changes in Expression of Cell Adhesion Molecules in Prostate Cancer. Eur. J. Cancer 1997, 33, 263–271.
  6. Cabodi, S.; del Pilar Camacho-Leal, M.; Di Stefano, P.; Defilippi, P. Integrin Signalling Adaptors: Not Only Figurants in the Cancer Story. Nat. Rev. Cancer 2010, 10, 858–870.
  7. Fromont, G.; Cussenot, O. The Integrin Signalling Adaptor P130CAS Is Also a Key Player in Prostate Cancer. Nat. Rev. Cancer 2011, 11, 227.
  8. Latil, A.; Bièche, I.; Pesche, S.; Valéri, A.; Fournier, G.; Cussenot, O.; Lidereau, R. VEGF Overexpression in Clinically Localized Prostate Tumors and Neuropilin-1 Overexpression in Metastatic Forms. Int. J. Cancer 2000, 89, 167–171.
  9. Cussenot, O.; Villette, J.M.; Cochand-Priollet, B.; Berthon, P. Evaluation and Clinical Value of Neuroendocrine Differentiation in Human Prostatic Tumors. Prostate Suppl. 1998, 8, 43–51.
  10. Lamb, A.D.; Warren, A.Y.; Neal, D.E. Pre-Malignant Disease in the Prostate. In Pre-Invasive Disease: Pathogenesis and Clinical Management; Fitzgerald, R.C., Ed.; Springer: New York, NY, USA, 2011; pp. 467–491. ISBN 978-1-4419-6694-0.
  11. De Marzo, A.M.; Nelson, W.G.; Meeker, A.K.; Coffey, D.S. Stem Cell Features of Benign and Malignant Prostate Epithelial Cells. J. Urol. 1998, 160, 2381–2392.
  12. Strand, D.W.; Goldstein, A.S. The Many Ways to Make a Luminal Cell and a Prostate Cancer Cell. Endocr. Relat. Cancer 2015, 22, T187–T197.
  13. Bakht, M.K.; Yamada, Y.; Ku, S.-Y.; Venkadakrishnan, V.B.; Korsen, J.A.; Kalidindi, T.M.; Mizuno, K.; Ahn, S.H.; Seo, J.-H.; Garcia, M.M.; et al. Landscape of Prostate-Specific Membrane Antigen Heterogeneity and Regulation in AR-Positive and AR-Negative Metastatic Prostate Cancer. Nat. Cancer 2023, 4, 699–715.
  14. Joseph, D.B.; Turco, A.E.; Vezina, C.M.; Strand, D.W. Progenitors in Prostate Development and Disease. Dev. Biol. 2021, 473, 50–58.
  15. Henry, G.H.; Malewska, A.; Joseph, D.B.; Malladi, V.S.; Lee, J.; Torrealba, J.; Mauck, R.J.; Gahan, J.C.; Raj, G.V.; Roehrborn, C.G.; et al. A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra. Cell Rep. 2018, 25, 3530–3542.e5.
  16. Joseph, D.B.; Henry, G.H.; Malewska, A.; Reese, J.C.; Mauck, R.J.; Gahan, J.C.; Hutchinson, R.C.; Mohler, J.L.; Roehrborn, C.G.; Strand, D.W. 5-Alpha Reductase Inhibitors Induce a Prostate Luminal to Club Cell Transition in Human Benign Prostatic Hyperplasia. J. Pathol. 2022, 256, 427–441.
  17. Letellier, G.; Perez, M.; Yacoub, M.; Levillain, P.; Cussenot, O.; Fromont, G. Epithelial Phenotypes in the Developing Human Prostate. J. Histochem. Cytochem. 2007, 55, 885–890.
  18. Roy, S.; Kaur, M.; Agarwal, C.; Tecklenburg, M.; Sclafani, R.A.; Agarwal, R. P21 and P27 Induction by Silibinin Is Essential for Its Cell Cycle Arrest Effect in Prostate Carcinoma Cells. Mol. Cancer Ther. 2007, 6, 2696–2707.
  19. Tsihlias, J.; Kapusta, L.R.; DeBoer, G.; Morava-Protzner, I.; Zbieranowski, I.; Bhattacharya, N.; Catzavelos, G.C.; Klotz, L.H.; Slingerland, J.M. Loss of Cyclin-Dependent Kinase Inhibitor P27Kip1 Is a Novel Prognostic Factor in Localized Human Prostate Adenocarcinoma. Cancer Res. 1998, 58, 542–548.
  20. De Marzo, A.; Meeker, A.; Zha, S.; Luo, J.; Nakayama, M.; Platz, E.; Isaacs, W.; Nelson, W. Human Prostate Cancer Precursors and Pathobiology. Urology 2003, 62, 55–62.
  21. Man, Y.; Mannion, C.; Jewett, A.; Hsiao, Y.-H.; Liu, A.; Semczuk, A.; Zarogoulidis, P.; Gapeev, A.B.; Cimadamore, A.; Lee, P.; et al. The Most Effective but Largely Ignored Target for Prostate Cancer Early Detection and Intervention. J. Cancer 2022, 13, 3463–3475.
  22. Tyekucheva, S.; Bowden, M.; Bango, C.; Giunchi, F.; Huang, Y.; Zhou, C.; Bondi, A.; Lis, R.; Van Hemelrijck, M.; Andrén, O.; et al. Stromal and Epithelial Transcriptional Map of Initiation Progression and Metastatic Potential of Human Prostate Cancer. Nat. Commun. 2017, 8, 420.
  23. Krušlin, B.; Ulamec, M.; Tomas, D. Prostate Cancer Stroma: An Important Factor in Cancer Growth and Progression. Bosn. J. Basic Med. Sci. 2015, 15, 1.
  24. Bahmad, H.F.; Jalloul, M.; Azar, J.; Moubarak, M.M.; Samad, T.A.; Mukherji, D.; Al-Sayegh, M.; Abou-Kheir, W. Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development. Front. Genet. 2021, 12, 652747.
  25. Yu, X.; Liu, R.; Gao, W.; Wang, X.; Zhang, Y. Single-Cell Omics Traces the Heterogeneity of Prostate Cancer Cells and the Tumor Microenvironment. Cell Mol. Biol. Lett. 2023, 28, 38.
  26. Kalluri, R. The Biology and Function of Fibroblasts in Cancer. Nat. Rev. Cancer 2016, 16, 582–598.
  27. Owen, J.S.; Clayton, A.; Pearson, H.B. Cancer-Associated Fibroblast Heterogeneity, Activation and Function: Implications for Prostate Cancer. Biomolecules 2022, 13, 67.
  28. Graham, M.K.; Chikarmane, R.; Wang, R.; Vaghasia, A.; Gupta, A.; Zheng, Q.; Wodu, B.; Pan, X.; Castagna, N.; Liu, J.; et al. Single-Cell Atlas of Epithelial and Stromal Cell Heterogeneity by Lobe and Strain in the Mouse Prostate. Prostate 2023, 83, 286–303.
  29. Owens, G.K. Regulation of Differentiation of Vascular Smooth Muscle Cells. Physiol. Rev. 1995, 75, 487–517.
  30. Ayala, G.; Tuxhorn, J.A.; Wheeler, T.M.; Frolov, A.; Scardino, P.T.; Ohori, M.; Wheeler, M.; Spitler, J.; Rowley, D.R. Reactive Stroma as a Predictor of Biochemical-Free Recurrence in Prostate Cancer. Clin. Cancer Res. 2003, 9, 4792–4801.
  31. Tuxhorn, J.A.; Ayala, G.E.; Smith, M.J.; Smith, V.C.; Dang, T.D.; Rowley, D.R. Reactive Stroma in Human Prostate Cancer: Induction of Myofibroblast Phenotype and Extracellular Matrix Remodeling. Clin. Cancer Res. 2002, 8, 2912–2923.
  32. Pederzoli, F.; Raffo, M.; Pakula, H.; Ravera, F.; Nuzzo, P.V.; Loda, M. “Stromal Cells in Prostate Cancer Pathobiology: Friends or Foes?”. Br. J. Cancer 2023, 128, 930–939.
  33. Goncharov, N.V.; Popova, P.I.; Avdonin, P.P.; Kudryavtsev, I.V.; Serebryakova, M.K.; Korf, E.A.; Avdonin, P.V. Markers of Endothelial Cells in Normal and Pathological Conditions. Biochem. (Mosc.) Suppl. Ser. A Membr. Cell Biol. 2020, 14, 167–183.
  34. Heidegger, I.; Fotakis, G.; Offermann, A.; Goveia, J.; Daum, S.; Salcher, S.; Noureen, A.; Timmer-Bosscha, H.; Schäfer, G.; Walenkamp, A.; et al. Comprehensive Characterization of the Prostate Tumor Microenvironment Identifies CXCR4/CXCL12 Crosstalk as a Novel Antiangiogenic Therapeutic Target in Prostate Cancer. Mol. Cancer 2022, 21, 132.
  35. Messex, J.K.; Liou, G.-Y. Impact of Immune Cells in the Tumor Microenvironment of Prostate Cancer Metastasis. Life 2023, 13, 333.
  36. Feng, D.; Xiong, Q.; Wei, Q.; Yang, L. Cellular Landscape of Tumour Microenvironment in Prostate Cancer. Immunology 2023, 168, 199–202.
  37. Chung, L.W.K.; Hsieh, C.-L.; Law, A.; Sung, S.-Y.; Gardner, T.A.; Egawa, M.; Matsubara, S.; Zhau, H.E. New Targets for Therapy in Prostate Cancer: Modulation of Stromal–Epithelial Interactions. Urology 2003, 62, 44–54.
  38. Wong, Y.C.; Wang, Y.Z. Growth Factors and Epithelial-Stromal Interactions in Prostate Cancer Development. In International Review of Cytology; Academic Press: Cambridge, MA, USA, 2000; Volume 199, pp. 65–116.
  39. Glabman, R.A.; Choyke, P.L.; Sato, N. Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy. Cancers 2022, 14, 3906.
  40. Bonollo, F.; Thalmann, G.N.; Kruithof-de Julio, M.; Karkampouna, S. The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis. Cancers 2020, 12, 1887.
  41. Yan, G.; Fukabori, Y.; Nikolaropoulos, S.; Wang, F.; McKeehan, W.L. Heparin-Binding Keratinocyte Growth Factor Is a Candidate Stromal-to-Epithelial-Cell Andromedin. Mol. Endocrinol. 1992, 6, 2123–2128.
  42. Nakano, K.; Fukabori, Y.; Itoh, N.; Lu, W.; Kan, M.; McKeehan, W.L.; Yamanaka, H. Androgen-Stimulated Human Prostate Epithelial Growth Mediated by Stromal-Derived Fibroblast Growth Factor-10. Endocr. J. 1999, 46, 405–413.
  43. Memarzadeh, S.; Xin, L.; Mulholland, D.J.; Mansukhani, A.; Wu, H.; Teitell, M.A.; Witte, O.N. Enhanced Paracrine FGF10 Expression Promotes Formation of Multifocal Prostate Adenocarcinoma and an Increase in Epithelial Androgen Receptor. Cancer Cell 2007, 12, 572–585.
  44. Thomson, A.A. Role of Androgens and Fibroblast Growth Factors in Prostatic Development. Reproduction 2001, 121, 187–195.
  45. Cunha, G.R.; Hayward, S.W.; Wang, Y.z.; Ricke, W.A. Role of the Stromal Microenvironment in Carcinogenesis of the Prostate. Int. J. Cancer 2003, 107, 1–10.
  46. Ropiquet, F.; Berthon, P.; Villette, J.M.; Le Brun, G.; Maitland, N.J.; Cussenot, O.; Fiet, J. Constitutive Expression of FGF2/BFGF in Non-Tumorigenic Human Prostatic Epithelial Cells Results in the Acquisition of a Partial Neoplastic Phenotype. Int. J. Cancer 1997, 72, 543–547.
  47. Mirzaei, S.; Paskeh, M.D.A.; Saghari, Y.; Zarrabi, A.; Hamblin, M.R.; Entezari, M.; Hashemi, M.; Aref, A.R.; Hushmandi, K.; Kumar, A.P.; et al. Transforming Growth Factor-Beta (TGF-β) in Prostate Cancer: A Dual Function Mediator? Int. J. Biol. Macromol. 2022, 206, 435–452.
  48. Figiel, S.; Vasseur, C.; Bruyere, F.; Rozet, F.; Maheo, K.; Fromont, G. Clinical Significance of Epithelial-Mesenchymal Transition Markers in Prostate Cancer. Hum. Pathol. 2017, 61, 26–32.
  49. Guido, C.; Whitaker-Menezes, D.; Capparelli, C.; Balliet, R.; Lin, Z.; Pestell, R.G.; Howell, A.; Aquila, S.; Andò, S.; Martinez-Outschoorn, U.; et al. Metabolic Reprogramming of Cancer-Associated Fibroblasts by TGF-β Drives Tumor Growth: Connecting TGF-β Signaling with “Warburg-like” Cancer Metabolism and L-Lactate Production. Cell Cycle 2012, 11, 3019–3035.
  50. Costanza, B.; Umelo, I.A.; Bellier, J.; Castronovo, V.; Turtoi, A. Stromal Modulators of TGF-β in Cancer. J. Clin. Med. 2017, 6, 7.
  51. Cai, C.; Balk, S.P. Intratumoral Androgen Biosynthesis in Prostate Cancer Pathogenesis and Response to Therapy. Endocr.-Relat. Cancer 2011, 18, R175–R182.
  52. Armandari, I.; Hamid, A.R.; Verhaegh, G.; Schalken, J. Intratumoral Steroidogenesis in Castration-Resistant Prostate Cancer: A Target for Therapy. Prostate Int. 2014, 2, 105–113.
  53. Figiel, S.; Pinault, M.; Domingo, I.; Guimaraes, C.; Guibon, R.; Besson, P.; Tavernier, E.; Blanchet, P.; Multigner, L.; Bruyère, F.; et al. Fatty Acid Profile in Peri-Prostatic Adipose Tissue and Prostate Cancer Aggressiveness in African-Caribbean and Caucasian Patients. Eur. J. Cancer 2018, 91, 107–115.
  54. Figiel, S.; Bery, F.; Chantôme, A.; Fontaine, D.; Pasqualin, C.; Maupoil, V.; Domingo, I.; Guibon, R.; Bruyère, F.; Potier-Cartereau, M.; et al. A Novel Calcium-Mediated EMT Pathway Controlled by Lipids: An Opportunity for Prostate Cancer Adjuvant Therapy. Cancers 2019, 11, 1814.
  55. Wu, X.; Daniels, G.; Lee, P.; Monaco, M.E. Lipid Metabolism in Prostate Cancer. Am. J. Clin. Exp. Urol. 2014, 2, 111–120.
  56. Compérat, E.; Wasinger, G.; Oszwald, A.; Kain, R.; Cancel-Tassin, G.; Cussenot, O. The Genetic Complexity of Prostate Cancer. Genes 2020, 11, 1396.
  57. Eastham, J.A.; Auffenberg, G.B.; Barocas, D.A.; Chou, R.; Crispino, T.; Davis, J.W.; Eggener, S.; Horwitz, E.M.; Kane, C.J.; Kirkby, E.; et al. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management. J. Urol. 2022, 208, 10–18.
  58. Overview|Prostate Cancer: Diagnosis and Management|Guidance|NICE. Available online: https://www.nice.org.uk/guidance/ng131 (accessed on 15 December 2021).
  59. Gleason, D.F. Classification of Prostatic Carcinomas. Cancer Chemother. Rep. 1966, 50, 125–128.
  60. Epstein, J.I.; Egevad, L.; Amin, M.B.; Delahunt, B.; Srigley, J.R.; Humphrey, P.A.; Grading Committee The 2014 International Society of Urological Pathology (ISUP). Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am. J. Surg. Pathol. 2016, 40, 244–252.
  61. Marra, G.; van Leenders, G.J.L.H.; Zattoni, F.; Kesch, C.; Rajwa, P.; Cornford, P.; van der Kwast, T.; van den Bergh, R.C.N.; Briers, E.; Van den Broeck, T.; et al. Impact of Epithelial Histological Types, Subtypes, and Growth Patterns on Oncological Outcomes for Patients with Nonmetastatic Prostate Cancer Treated with Curative Intent: A Systematic Review. Eur. Urol. 2023, 84, 65–85.
  62. Cussenot, O.; Cancel-Tassin, G.; Comperat, E.; Benbouzid, S.; Lamb, A. Total Pelvic Exenteration Surgery for Loco-Regionally Advanced Prostate Cancer, Is It Justifiable? BJU Int. 2022, 130, 582–585.
  63. Ranasinha, N.; Omer, A.; Philippou, Y.; Harriss, E.; Davies, L.; Chow, K.; Chetta, P.M.; Erickson, A.; Rajakumar, T.; Mills, I.G.; et al. Ductal Adenocarcinoma of the Prostate: A Systematic Review and Meta-Analysis of Incidence, Presentation, Prognosis, and Management. BJUI Compass 2021, 2, 13–23.
  64. Rathod, S.G.; Jaiswal, D.G.; Bindu, R.S. Diagnostic Utility of Triple Antibody (AMACR, HMWCK and P63) Stain in Prostate Neoplasm. J. Fam. Med. Prim. Care 2019, 8, 2651–2655.
  65. Mytsyk, Y.; Nakonechnyi, Y.; Dosenko, V.; Kowal, P.; Pietrus, M.; Gazdikova, K.; Labudova, M.; Caprnda, M.; Prosecky, R.; Dragasek, J.; et al. The Performance and Limitations of PCA3, TMPRSS2:ERG, HOXC6 and DLX1 Urinary Markers Combined in the Improvement of Prostate Cancer Diagnostics. Clin. Biochem. 2023, 116, 120–127.
  66. Rouprêt, M.; Hupertan, V.; Yates, D.R.; Catto, J.W.F.; Rehman, I.; Meuth, M.; Ricci, S.; Lacave, R.; Cancel-Tassin, G.; de la Taille, A.; et al. Molecular Detection of Localized Prostate Cancer Using Quantitative Methylation-Specific PCR on Urinary Cells Obtained Following Prostate Massage. Clin. Cancer Res. 2007, 13, 1720–1725.
  67. Thuret, R.; Chantrel-Groussard, K.; Azzouzi, A.-R.; Villette, J.-M.; Guimard, S.; Teillac, P.; Berthon, P.; Houlgatte, A.; Latil, A.; Cussenot, O. Clinical Relevance of Genetic Instability in Prostatic Cells Obtained by Prostatic Massage in Early Prostate Cancer. Br. J. Cancer 2005, 92, 236–240.
  68. Cornu, J.-N.; Cancel-Tassin, G.; Egrot, C.; Gaffory, C.; Haab, F.; Cussenot, O. Urine TMPRSS2:ERG Fusion Transcript Integrated with PCA3 Score, Genotyping, and Biological Features Are Correlated to the Results of Prostatic Biopsies in Men at Risk of Prostate Cancer. Prostate 2013, 73, 242–249.
  69. Haffner, M.C.; Zwart, W.; Roudier, M.P.; True, L.D.; Nelson, W.G.; Epstein, J.I.; De Marzo, A.M.; Nelson, P.S.; Yegnasubramanian, S. Genomic and Phenotypic Heterogeneity in Prostate Cancer. Nat. Rev. Urol. 2021, 18, 79–92.
  70. Erickson, A.; Hayes, A.; Rajakumar, T.; Verrill, C.; Bryant, R.J.; Hamdy, F.C.; Wedge, D.C.; Woodcock, D.J.; Mills, I.G.; Lamb, A.D. A Systematic Review of Prostate Cancer Heterogeneity: Understanding the Clonal Ancestry of Multifocal Disease. Eur. Urol. Oncol. 2021, 4, 358–369.
  71. Berthon, P.; Dimitrov, T.; Stower, M.; Cussenot, O.; Maitland, N.J. A Microdissection Approach to Detect Molecular Markers during Progression of Prostate Cancer. Br. J. Cancer 1995, 72, 946–951.
  72. Bronkema, C.; Arora, S.; Sood, A.; Dalela, D.; Keeley, J.; Borchert, A.; Baumgarten, L.; Rogers, C.G.; Peabody, J.O.; Menon, M.; et al. Rare Histological Variants of Prostate Adenocarcinoma: A National Cancer Database Analysis. J. Urol. 2020, 204, 260–266.
  73. Grignon, D.J. Unusual Subtypes of Prostate Cancer. Mod. Pathol. 2004, 17, 316–327.
  74. Baraban, E.; Epstein, J. Prostate Cancer: Update on Grading and Reporting. Surg. Pathol. Clin. 2022, 15, 579–589.
  75. Cancer Genome Atlas Research Network. The Molecular Taxonomy of Primary Prostate Cancer. Cell 2015, 163, 1011–1025.
  76. Rebello, R.J.; Oing, C.; Knudsen, K.E.; Loeb, S.; Johnson, D.C.; Reiter, R.E.; Gillessen, S.; Van der Kwast, T.; Bristow, R.G. Prostate Cancer. Nat. Rev. Dis. Primers 2021, 7, 1–27.
  77. Testa, U.; Castelli, G.; Pelosi, E. Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications. Medicines 2019, 6, 82.
  78. Schoenborn, J.R.; Nelson, P.; Fang, M. Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification. Clin. Cancer Res. 2013, 19, 4058–4066.
  79. Shin, H.J.; Hua, J.T.; Li, H. Recent Advances in Understanding DNA Methylation of Prostate Cancer. Front. Oncol. 2023, 13, 1182727.
  80. Tomlins, S.A.; Rhodes, D.R.; Perner, S.; Dhanasekaran, S.M.; Mehra, R.; Sun, X.-W.; Varambally, S.; Cao, X.; Tchinda, J.; Kuefer, R.; et al. Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer. Science 2005, 310, 644–648.
  81. Rubin, M.A.; Maher, C.A.; Chinnaiyan, A.M. Common Gene Rearrangements in Prostate Cancer. J. Clin. Oncol. 2011, 29, 3659–3668.
  82. St. John, J.; Powell, K.; Conley-LaComb, M.K.; Chinni, S.R. TMPRSS2-ERG Fusion Gene Expression in Prostate Tumor Cells and Its Clinical and Biological Significance in Prostate Cancer Progression. J. Cancer Sci. Ther. 2012, 4, 94–101.
  83. Iljin, K.; Wolf, M.; Edgren, H.; Gupta, S.; Kilpinen, S.; Skotheim, R.I.; Peltola, M.; Smit, F.; Verhaegh, G.; Schalken, J.; et al. TMPRSS2 Fusions with Oncogenic ETS Factors in Prostate Cancer Involve Unbalanced Genomic Rearrangements and Are Associated with HDAC1 and Epigenetic Reprogramming. Cancer Res. 2006, 66, 10242–10246.
  84. Burdelski, C.; Kleinhans, S.; Kluth, M.; Hube-Magg, C.; Minner, S.; Koop, C.; Graefen, M.; Heinzer, H.; Tsourlakis, M.C.; Wilczak, W.; et al. Reduced AZGP1 Expression Is an Independent Predictor of Early PSA Recurrence and Associated with ERG-Fusion Positive and PTEN Deleted Prostate Cancers. Int. J. Cancer 2016, 138, 1199–1206.
  85. Massoner, P.; Kugler, K.G.; Unterberger, K.; Kuner, R.; Mueller, L.A.J.; Fälth, M.; Schäfer, G.; Seifarth, C.; Ecker, S.; Verdorfer, I.; et al. Characterization of Transcriptional Changes in ERG Rearrangement-Positive Prostate Cancer Identifies the Regulation of Metabolic Sensors Such as Neuropeptide Y. PLoS ONE 2013, 8, e55207.
  86. Alhamar, M.; Tudor Vladislav, I.; Smith, S.C.; Gao, Y.; Cheng, L.; Favazza, L.A.; Alani, A.M.; Ittmann, M.M.; Riddle, N.D.; Whiteley, L.J.; et al. Gene Fusion Characterisation of Rare Aggressive Prostate Cancer Variants—Adenosquamous Carcinoma, Pleomorphic Giant-Cell Carcinoma, and Sarcomatoid Carcinoma: An Analysis of 19 Cases. Histopathology 2020, 77, 890–899.
  87. Kamoun, A.; Cancel-Tassin, G.; Fromont, G.; Elarouci, N.; Armenoult, L.; Ayadi, M.; Irani, J.; Leroy, X.; Villers, A.; Fournier, G.; et al. Comprehensive Molecular Classification of Localized Prostate Adenocarcinoma Reveals a Tumour Subtype Predictive of Non-Aggressive Disease. Ann. Oncol. 2018, 29, 1814–1821.
  88. Léon, P.; Cancel-Tassin, G.; Drouin, S.; Audouin, M.; Varinot, J.; Comperat, E.; Cathelineau, X.; Rozet, F.; Vaessens, C.; Stone, S.; et al. Comparison of Cell Cycle Progression Score with Two Immunohistochemical Markers (PTEN and Ki-67) for Predicting Outcome in Prostate Cancer after Radical Prostatectomy. World J. Urol. 2018, 36, 1495–1500.
  89. Pesche, S.; Latil, A.; Muzeau, F.; Cussenot, O.; Fournier, G.; Longy, M.; Eng, C.; Lidereau, R. PTEN/MMAC1/TEP1 Involvement in Primary Prostate Cancers. Oncogene 1998, 16, 2879–2883.
  90. Wise, H.M.; Hermida, M.A.; Leslie, N.R. Prostate Cancer, PI3K, PTEN and Prognosis. Clin. Sci. 2017, 131, 197–210.
  91. Ceder, Y.; Bjartell, A.; Culig, Z.; Rubin, M.A.; Tomlins, S.; Visakorpi, T. The Molecular Evolution of Castration-Resistant Prostate Cancer. Eur. Urol. Focus 2016, 2, 506–513.
  92. Sprenger, C.C.T.; Plymate, S.R. The Link between Androgen Receptor Splice Variants and Castration Resistant Prostate Cancer. Horm. Cancer 2014, 5, 207–217.
  93. Fujita, K.; Nonomura, N. Role of Androgen Receptor in Prostate Cancer: A Review. World J. Mens. Health 2019, 37, 288–295.
  94. Kubota, Y.; Shuin, T.; Uemura, H.; Fujinami, K.; Miyamoto, H.; Torigoe, S.; Dobashi, Y.; Kitamura, H.; Iwasaki, Y.; Danenberg, K. Tumor Suppressor Gene P53 Mutations in Human Prostate Cancer. Prostate 1995, 27, 18–24.
  95. Kir, G.; Cecikoglu, G.E.; Olgun, Z.C.; Kazan, H.O.; Yildirim, A. PTEN Loss and PD-L1 Expression of Different Histological Patterns of Prostate Cancer. Pathol. Res. Pract. 2022, 229, 153738.
  96. Merkens, L.; Sailer, V.; Lessel, D.; Janzen, E.; Greimeier, S.; Kirfel, J.; Perner, S.; Pantel, K.; Werner, S.; von Amsberg, G. Aggressive Variants of Prostate Cancer: Underlying Mechanisms of Neuroendocrine Transdifferentiation. J. Exp. Clin. Cancer Res. 2022, 41, 46.
  97. Zhu, Z.; Liu, X.; Li, W.; Wen, Z.; Ji, X.; Zhou, R.; Tuo, X.; Chen, Y.; Gong, X.; Liu, G.; et al. A Rare Multiple Primary Sarcomatoid Carcinoma (SCA) of Small Intestine Harboring Driver Gene Mutations: A Case Report and a Literature Review. Transl. Cancer Res. 2021, 10, 1150–1161.
  98. Hesterberg, A.B.; Gordetsky, J.B.; Hurley, P.J. Cribriform Prostate Cancer: Clinical Pathologic and Molecular Considerations. Urology 2021, 155, 47–54.
  99. Baraban, E.; Erak, E.; Fatima, A.; Akbari, A.; Zhao, J.; Fletcher, S.A.; Bhanji, Y.; de la Calle, C.M.; Mamawala, M.; Landis, P.; et al. Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer. J. Urol. 2023, 210, 99–107.
  100. Kweldam, C.F.; Wildhagen, M.F.; Steyerberg, E.W.; Bangma, C.H.; van der Kwast, T.H.; van Leenders, G.J.L.H. Cribriform Growth Is Highly Predictive for Postoperative Metastasis and Disease-Specific Death in Gleason Score 7 Prostate Cancer. Mod. Pathol. 2015, 28, 457–464.
  101. Downes, M.R.; Xu, B.; van der Kwast, T.H. Gleason Grade Patterns in Nodal Metastasis and Corresponding Prostatectomy Specimens: Impact on Patient Outcome. Histopathology 2019, 75, 715–722.
  102. Greenland, N.Y.; Cooperberg, M.R.; Wong, A.C.; Chan, E.; Carroll, P.R.; Simko, J.P.; Stohr, B.A. Molecular Risk Classifier Score and Biochemical Recurrence Risk Are Associated with Cribriform Pattern Type in Gleason 3+4=7 Prostate Cancer. Investig. Clin. Urol. 2022, 63, 27–33.
  103. Halstuch, D.; Ber, Y.; Margel, D. Screening, Active Surveillance, and Treatment of Localized Prostate Cancer Among Carriers of Germline BRCA Mutations. Eur. Urol. Focus 2020, 6, 212–214.
  104. Zong, Y.; Xin, L.; Goldstein, A.S.; Lawson, D.A.; Teitell, M.A.; Witte, O.N. ETS Family Transcription Factors Collaborate with Alternative Signaling Pathways to Induce Carcinoma from Adult Murine Prostate Cells. Proc. Natl. Acad. Sci. USA 2009, 106, 12465–12470.
  105. Abida, W.; Cyrta, J.; Heller, G.; Prandi, D.; Armenia, J.; Coleman, I.; Cieslik, M.; Benelli, M.; Robinson, D.; Van Allen, E.M.; et al. Genomic Correlates of Clinical Outcome in Advanced Prostate Cancer. Proc. Natl. Acad. Sci. USA 2019, 116, 11428–11436.
  106. Cucchiara, V.; Cooperberg, M.R.; Dall’Era, M.; Lin, D.W.; Montorsi, F.; Schalken, J.A.; Evans, C.P. Genomic Markers in Prostate Cancer Decision Making. Eur. Urol. 2018, 73, 572–582.
  107. Kretschmer, A.; Tilki, D. Biomarkers in Prostate Cancer—Current Clinical Utility and Future Perspectives. Crit. Rev. Oncol. Hematol. 2017, 120, 180–193.
  108. Renard-Penna, R.; Cancel-Tassin, G.; Comperat, E.; Roupret, M.; Mozer, P.; Cussenot, O. Functional Magnetic Resonance Imaging and Molecular Pathology at the Crossroad of the Management of Early Prostate Cancer. World J. Urol. 2015, 33, 929–936.
  109. Cuzick, J.; Berney, D.M.; Fisher, G.; Mesher, D.; Møller, H.; Reid, J.E.; Perry, M.; Park, J.; Younus, A.; Gutin, A.; et al. Prognostic Value of a Cell Cycle Progression Signature for Prostate Cancer Death in a Conservatively Managed Needle Biopsy Cohort. Br. J. Cancer 2012, 106, 1095–1099.
  110. Kuhl, V.; Clegg, W.; Meek, S.; Lenz, L.; Flake, D.D.; Ronan, T.; Kornilov, M.; Horsch, D.; Scheer, M.; Farber, D.; et al. Development and Validation of a Cell Cycle Progression Signature for Decentralized Testing of Men with Prostate Cancer. Biomark. Med. 2022, 16, 449–459.
  111. Klein, E.A.; Cooperberg, M.R.; Magi-Galluzzi, C.; Simko, J.P.; Falzarano, S.M.; Maddala, T.; Chan, J.M.; Li, J.; Cowan, J.E.; Tsiatis, A.C.; et al. A 17-Gene Assay to Predict Prostate Cancer Aggressiveness in the Context of Gleason Grade Heterogeneity, Tumor Multifocality, and Biopsy Undersampling. Eur. Urol. 2014, 66, 550–560.
  112. Cullen, J.; Rosner, I.L.; Brand, T.C.; Zhang, N.; Tsiatis, A.C.; Moncur, J.; Ali, A.; Chen, Y.; Knezevic, D.; Maddala, T.; et al. A Biopsy-Based 17-Gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-Risk Prostate Cancer. Eur. Urol. 2015, 68, 123–131.
  113. Heinlein, C.A.; Chang, C. Androgen Receptor in Prostate Cancer. Endocr. Rev. 2004, 25, 276–308.
  114. Aurilio, G.; Cimadamore, A.; Mazzucchelli, R.; Lopez-Beltran, A.; Verri, E.; Scarpelli, M.; Massari, F.; Cheng, L.; Santoni, M.; Montironi, R. Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications. Cells 2020, 9, 2653.
  115. Zhu, M.-L.; Kyprianou, N. Role of Androgens and the Androgen Receptor in Epithelial-Mesenchymal Transition and Invasion of Prostate Cancer Cells. FASEB J. 2010, 24, 769–777.
  116. Lamb, A.D.; Massie, C.E.; Neal, D.E. The Transcriptional Programme of the Androgen Receptor (AR) in Prostate Cancer. BJU Int. 2014, 113, 358–366.
  117. Bonkhoff, H.; Remberger, K. Widespread Distribution of Nuclear Androgen Receptors in the Basal Cell Layer of the Normal and Hyperplastic Human Prostate. Vichows Arch. A Pathol. Anat. 1993, 422, 35–38.
  118. Berthon, P.; Waller, A.S.; Villette, J.M.; Loridon, L.; Cussenot, O.; Maitland, N.J. Androgens Are Not a Direct Requirement for the Proliferation of Human Prostatic Epithelium in Vitro. Int. J. Cancer 1997, 73, 910–916.
  119. Roy, A.K.; Tyagi, R.K.; Song, C.S.; Lavrovsky, Y.; Ahn, S.C.; Oh, T.S.; Chatterjee, B. Androgen Receptor: Structural Domains and Functional Dynamics after Ligand-Receptor Interaction. Ann. N. Y. Acad. Sci. 2001, 949, 44–57.
  120. Chung, C.; Abboud, K. Targeting the Androgen Receptor Signaling Pathway in Advanced Prostate Cancer. Am. J. Health-Syst. Pharm. 2022, 79, 1224–1235.
  121. Jin, H.-J.; Kim, J.; Yu, J. Androgen Receptor Genomic Regulation. Transl. Androl. Urol. 2013, 2, 158–177.
  122. Norris, J.D.; Chang, C.-Y.; Wittmann, B.M.; Kunder, R.S.; Cui, H.; Fan, D.; Joseph, J.D.; McDonnell, D.P. The Homeodomain Protein HOXB13 Regulates the Cellular Response to Androgens. Mol. Cell 2009, 36, 405–416.
  123. Tan, P.Y.; Chang, C.W.; Chng, K.R.; Wansa, K.D.S.A.; Sung, W.-K.; Cheung, E. Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival. Mol. Cell Biol. 2012, 32, 399–414.
  124. Perez-Stable, C.M.; Pozas, A.; Roos, B.A. A Role for GATA Transcription Factors in the Androgen Regulation of the Prostate-Specific Antigen Gene Enhancer. Mol. Cell Endocrinol. 2000, 167, 43–53.
  125. Wang, Q.; Li, W.; Liu, X.S.; Carroll, J.S.; Jänne, O.A.; Keeton, E.K.; Chinnaiyan, A.M.; Pienta, K.J.; Brown, M. A Hierarchical Network of Transcription Factors Governs Androgen Receptor-Dependent Prostate Cancer Growth. Mol. Cell 2007, 27, 380–392.
  126. Massie, C.E.; Lynch, A.; Ramos-Montoya, A.; Boren, J.; Stark, R.; Fazli, L.; Warren, A.; Scott, H.; Madhu, B.; Sharma, N.; et al. The Androgen Receptor Fuels Prostate Cancer by Regulating Central Metabolism and Biosynthesis. EMBO J. 2011, 30, 2719–2733.
  127. Takayama, K.; Inoue, S. Transcriptional Network of Androgen Receptor in Prostate Cancer Progression. Int. J. Urol. 2013, 20, 756–768.
  128. Ramos-Montoya, A.; Lamb, A.D.; Russell, R.; Carroll, T.; Jurmeister, S.; Galeano-Dalmau, N.; Massie, C.E.; Boren, J.; Bon, H.; Theodorou, V.; et al. HES6 Drives a Critical AR Transcriptional Programme to Induce Castration-Resistant Prostate Cancer through Activation of an E2F1-Mediated Cell Cycle Network. EMBO Mol. Med. 2014, 6, 651–661.
  129. Wu, L.; Runkle, C.; Jin, H.-J.; Yu, J.; Li, J.; Yang, X.; Kuzel, T.; Lee, C.; Yu, J. CCN3/NOV Gene Expression in Human Prostate Cancer Is Directly Suppressed by the Androgen Receptor. Oncogene 2014, 33, 504–513.
  130. Murillo-Garzón, V.; Kypta, R. WNT Signalling in Prostate Cancer. Nat. Rev. Urol. 2017, 14, 683–696.
  131. Wang, C.; Chen, Q.; Xu, H. Wnt/β-Catenin Signal Transduction Pathway in Prostate Cancer and Associated Drug Resistance. Discov. Oncol. 2021, 12, 40.
  132. Chen, G.; Shukeir, N.; Potti, A.; Sircar, K.; Aprikian, A.; Goltzman, D.; Rabbani, S.A. Up-Regulation of Wnt-1 and Beta-Catenin Production in Patients with Advanced Metastatic Prostate Carcinoma: Potential Pathogenetic and Prognostic Implications. Cancer 2004, 101, 1345–1356.
  133. Grasso, C.S.; Wu, Y.-M.; Robinson, D.R.; Cao, X.; Dhanasekaran, S.M.; Khan, A.P.; Quist, M.J.; Jing, X.; Lonigro, R.J.; Brenner, J.C.; et al. The Mutational Landscape of Lethal Castration-Resistant Prostate Cancer. Nature 2012, 487, 239–243.
  134. Robinson, D.; Van Allen, E.M.; Wu, Y.-M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.-M.; Montgomery, B.; Taplin, M.-E.; Pritchard, C.C.; Attard, G.; et al. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell 2015, 161, 1215–1228.
  135. Li, X.; Placencio, V.; Iturregui, J.M.; Uwamariya, C.; Sharif-Afshar, A.-R.; Koyama, T.; Hayward, S.W.; Bhowmick, N.A. Prostate Tumor Progression Is Mediated by a Paracrine TGF-Beta/Wnt3a Signaling Axis. Oncogene 2008, 27, 7118–7130.
  136. Zong, Y.; Huang, J.; Sankarasharma, D.; Morikawa, T.; Fukayama, M.; Epstein, J.I.; Chada, K.K.; Witte, O.N. Stromal Epigenetic Dysregulation Is Sufficient to Initiate Mouse Prostate Cancer via Paracrine Wnt Signaling. Proc. Natl. Acad. Sci. USA 2012, 109, E3395–E3404.
  137. Dakhova, O.; Ozen, M.; Creighton, C.J.; Li, R.; Ayala, G.; Rowley, D.; Ittmann, M. Global Gene Expression Analysis of Reactive Stroma in Prostate Cancer. Clin. Cancer Res. 2009, 15, 3979–3989.
  138. Yu, X.; Wang, Y.; DeGraff, D.J.; Wills, M.L.; Matusik, R.J. Wnt/β-Catenin Activation Promotes Prostate Tumor Progression in a Mouse Model. Oncogene 2011, 30, 1868–1879.
  139. Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-MTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507.
  140. Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; et al. Integrative Genomic Profiling of Human Prostate Cancer. Cancer Cell 2010, 18, 11–22.
  141. Armenia, J.; Wankowicz, S.A.M.; Liu, D.; Gao, J.; Kundra, R.; Reznik, E.; Chatila, W.K.; Chakravarty, D.; Han, G.C.; Coleman, I.; et al. The Long Tail of Oncogenic Drivers in Prostate Cancer. Nat. Genet. 2018, 50, 645–651.
  142. He, Y.; Xu, W.; Xiao, Y.-T.; Huang, H.; Gu, D.; Ren, S. Targeting Signaling Pathways in Prostate Cancer: Mechanisms and Clinical Trials. Signal Transduct. Target. Ther. 2022, 7, 198.
  143. Rodríguez-Berriguete, G.; Fraile, B.; Martínez-Onsurbe, P.; Olmedilla, G.; Paniagua, R.; Royuela, M. MAP Kinases and Prostate Cancer. J. Signal Transduct. 2012, 2012, 169170.
  144. Crumbaker, M.; Khoja, L.; Joshua, A.M. AR Signaling and the PI3K Pathway in Prostate Cancer. Cancers 2017, 9, 34.
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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Sandy Figiel
,
Géraldine Cancel-Tassin
,
Ian G. Mills
,
Alastair D. Lamb
,
Gaelle Fromont
,
Olivier Cussenot
View Times: 207
Revisions: 2 times (View History)
Update Date: 27 Oct 2023
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