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Molecular biology of bladder cancer

Molecular biology of bladder cancer
Authors:
Richard J Cote, MD, FRCPath
Anirban P Mitra, MD, PhD
Section Editor:
Seth P Lerner, MD
Deputy Editor:
Sonali M Shah, MD
Literature review current through: Jan 2024.
This topic last updated: Dec 15, 2023.

INTRODUCTION — Worldwide, cancer of the urinary bladder accounts for approximately 570,000 new cases and over 200,000 deaths annually [1]. Although there have been improvements in detection, treatment, and surveillance of bladder cancer, the overall prognosis for resectable bladder cancer has not improved [2].

The molecular subtypes of bladder cancer and molecular alterations that occur in bladder cancer are presented there. The pathology, clinical presentation and diagnosis, and management of bladder cancer are discussed separately.

●(See "Pathology of bladder neoplasms".)

●(See "Clinical presentation, diagnosis, and staging of bladder cancer".)

●(See "Overview of the initial approach and management of urothelial bladder cancer".)

●(See "Non-urothelial bladder cancer".)

MOLECULAR SUBTYPES OF BLADDER CANCER — Bladder cancer can largely present as two unique phenotypes: a noninvasive variety where cancer cells remain in the urothelial layer, and an invasive variety where they invade the subepithelial connective tissue and beyond [3]. Development and progression of bladder cancer through these stages involves genetic alterations affecting key cellular survival pathways.

Noninvasive cancer can be further subdivided into exophytic papillary (Ta) tumors and carcinoma in situ (CIS), each of which is associated with a unique pattern of molecular alterations.

Exophytic papillary tumors — Ta tumors are noninvasive and recur locally after resection. Ta tumors potentially harbor alterations that are distinct from CIS and invasive (T1 to T4) cancers, although it has been suggested that the pathways may not be mutually exclusive [4,5]. For example, low-grade Ta tumors are associated with receptor tyrosine kinase-Ras activation, specifically with Harvey rat sarcoma viral oncogene homolog (HRAS) and fibroblast growth factor receptor 3 (FGFR3) mutations [6-8]. High-grade Ta tumors are associated with p16INK4a homozygous deletion and a much lower frequency of FGFR3 mutations [9].

Carcinoma in situ and invasive tumors — CIS has a high propensity for invasion if left untreated. Tumor protein p53 (TP53) and retinoblastoma (RB) alterations are more characteristic of CIS and invasive tumors [10]. When the occasional papillary tumor does become invasive, it is often due to additional p53 pathway alterations. Muscle-invasive (T2 to T4) tumors are characterized by alterations in vascular endothelial growth factors (VEGFs), cadherins, and matrix metalloproteinases (MMPs), which remodel the extracellular matrix and promote angiogenesis and metastasis [4].

Subtypes defined by gene expression profiling — Other studies have used gene expression profiling to propose other novel subtypes [11], including one report that described three subtypes of muscle-invasive disease akin to genetic features with established breast cancer subtypes, which they described as basal, luminal, and p53-like tumors [12].

Additionally, integrated multiplatform analyses of mRNA, miRNA, long non-coding RNA (lncRNA), DNA methylation, copy number, protein expression, and whole-genome and whole-exome sequencing by The Cancer Genome Atlas Research Network stratified muscle-invasive disease into five subtypes (luminal, luminal-papillary, luminal-infiltrated, basal/squamous, and neuronal), with associated potential treatment strategies for each subtype [13].

The Bladder Cancer Molecular Taxonomy Group has identified a set of six molecular classes of muscle-invasive bladder cancer: luminal papillary, luminal-nonspecified, luminal-unstable, stroma-rich, basal/squamous, and neuroendocrine-like [14]. These classes are characterized by unique oncogenic mechanisms, infiltration by immune and stromal cells, histologic and clinical characteristics, and outcomes.

PATHWAY-SPECIFIC MOLECULAR ALTERATIONS — The pathogenesis of bladder cancer is influenced by alterations occurring in specific molecular pathways that lead to uncontrolled cellular division. Such molecular alterations may lend themselves to therapeutic interventions [15-19].

Regulation of the cell cycle — Pathways controlling the cell cycle are the most well-characterized in bladder cancer [20]. The cell cycle is primarily controlled by the p53 and retinoblastoma (RB) mechanisms that interact with mediators of apoptosis and gene regulation.

●p53 – p53 is encoded on chromosome 17p13.1 and inhibits cell-cycle progression by transcriptionally activating p21WAF1/CIP1 [21]. Although invasive tumors generally have loss of a single allele, mutation in the remaining allele results in tumor protein p53 (TP53) inactivation [22]. Wildtype p53 has a half-life of under 30 minutes that does not allow its accumulation in the cell nucleus [23]. However, mutant p53 is resistant to degradation, resulting in increased intranuclear accumulation that is detectable by immunohistochemistry.

Several retrospective studies have reported on the prognostic value of p53 nuclear accumulation, especially following radical cystectomy [24-29]. The rate of p53 alterations in primary tumors increases progressively from normal urothelium to non-muscle-invasive tumors, to muscle-invasive disease and metastatic nodes [30-32]. Analysis of muscle-invasive tumors by The Cancer Genome Atlas Research Network noted TP53 function to be inactivated in nearly 76 percent of samples [15]. However, the use of p53 as a prognostic marker is not clinically established. This may be explained, at least in part, by discordance in p53 nuclear accumulation and TP53 mutations [33]. A phase III trial designed to examine the benefit of stratifying organ-confined invasive bladder cancer patients based on p53 status for adjuvant cisplatin-based chemotherapy could not confirm its prognostic value or association with therapeutic response [34]. Limitations of this trial included a high patient refusal rate, lower than expected event rate, and failure to receive assigned therapy.

●p21 – p21 is a cyclin-dependent kinase (CDK) inhibitor that is transcriptionally regulated by p53. p53 alterations can result in loss of p21 expression, thereby influencing tumor progression [10]. Loss of p21 expression can predict disease progression, and maintenance of its expression can abrogate the effects of altered p53 [35]. p21 has been shown to predict recurrence and cancer-specific mortality in muscle-invasive disease [32]. The prognostic value of p21 may be most useful in patients with pT2-3N0 disease, especially when combined with other markers [30].

●Mdm2 – Mouse double-minute 2 homolog (Mdm2) participates in an autoregulatory feedback loop with p53, whereby increases in p53 upregulate MDM2, resulting in proteasomal p53 degradation and subsequent downregulation of Mdm2. The frequency of MDM2 amplifications in bladder cancer increases with higher tumor stage and grade [36].

●RB – RB is a cell-cycle regulatory protein, and its dephosphorylation sequesters E2F. CDKs phosphorylate RB, thereby releasing E2F, leading to transcription of genes required for DNA synthesis. Inactivating RB mutations have been confirmed in bladder tumors [37]. In combination with other cell-cycle proteins, RB expression has also been noted to be prognostic [27,28]. CDK inhibitors such as p21, p16, and p27 negatively regulate CDKs, thereby acting as tumor suppressors. p27 underexpression has been associated with advanced bladder adenocarcinomas [38]. p27 alterations have also been linked with shortened disease-free and overall survival [39]. p27 alterations in combination with other immunohistochemical markers improved the predictive value of a nomogram in pT1 patients who underwent radical cystectomy [40]. Combined immunohistochemical assessment of such cell cycle markers can improve predictive accuracies in patients treated with radical cystectomy, thereby improving risk stratification [41,42].

Apoptosis pathways — Apoptosis is a complex process involving coordination of multiple pathways leading to programmed cell death by activating caspases that cleave cellular substrates.

●Caspase-3 – Worse prognosis has been associated with low expression of Caspase-3 [43].

●Survivin – Survivin blocks caspase activity, thereby inhibiting apoptosis. It is overexpressed in more than 60 percent of bladder cancer cases (particularly more advanced disease) [44]. Survivin overexpression has been associated with disease recurrence and higher cancer-specific mortality [43]. In one study, incorporation of survivin expression improved the accuracy of standard clinical features for predicting disease recurrence and cancer-specific survival in patients with pT1-3N0M0 disease [45].

●The B-cell lymphoma 2 (Bcl-2) family of proteins – The Bcl-2 family includes antiapoptotic members such as Bcl-2 as well as proapoptotic members such as BCL2-associated X protein (Bax) and BCL2-associated agonist of cell death (Bad). Bcl-2 overexpression is associated with poor prognosis in bladder cancer patients treated with radiotherapy or chemoradiotherapy [46,47]. Its overexpression is also associated with worse survival and lower response rates to chemotherapy [48]. Combined aberrations in Mdm2, p53, and Bcl-2 have been shown to correspond with poor survival [49]. Conversely, Bax is a favorable prognosticator in invasive disease [50-52]. Bax mediates its proapoptotic role by activating apoptotic protease activating factor 1 (Apaf-1) [53]. Apaf-1 underexpression is associated with higher mortality [54].

Cell signaling and gene regulation — Cell-surface receptors modulate external signals to nuclei. Aberrations in these receptors deregulate gene expression, thereby giving rise to dysregulated cellular proliferation.

●FGFR family members – Activating fibroblast growth factor receptor 3 (FGFR3) mutations are the most extensively studied FGFR genetic aberrations in bladder cancer, with 60 to 70 percent of low-grade papillary Ta tumors harboring them [55,56]. This results in activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. FGFR inhibitors are used to treat metastatic urothelial carcinoma of the bladder and urinary tract. (See "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract", section on 'FGFR mutation positive'.)

●MAPK pathway members – Harvey rat sarcoma viral oncogene homolog (HRAS) expression has been associated with noninvasive cancer recurrence at initial presentation [57]. Mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3) is a member of the MAPK pathway that activates key effectors in cell signaling and was identified as part of a prognostic signature for high-risk bladder cancer, which was externally validated [58].

●Sex hormone receptors – It has been hypothesized that differing expression of sex hormone receptors explains why bladder cancer behaves differently between males and females, but data are limited [59]. For all patients, lower levels of estrogen receptor-beta expression have been associated with better progression-free survival rates in patients with noninvasive disease [60,61], while higher levels have been associated with more advanced tumors [62]. By contrast, androgen receptor expression has been seen in some studies to inversely correlate with pathologic stage and grade [60,63], while other studies have not observed an association [64].

●Janus kinase family members – Janus kinase is a family of kinases that mediate multiple signaling pathways by activation of the signal transducer and activator of transcription (STAT) pathway. STAT3 expression, used in conjunction with other molecular and clinical measures, can predict recurrence and survival in patients with bladder cancer [65].

●MRE11 – Meiotic recombination 11 (MRE11) is a nuclear protein that regulates telomere length maintenance and DNA double-strand break repair. MRE11 underexpression in bladder cancer has been associated with worse cancer-specific survival; high MRE11 expression in patients undergoing radical radiotherapy for muscle-invasive cancer has been associated with better outcomes [66,67]. Certain germline MRE11 variants may predict radiation response in muscle-invasive disease, according to one study, but more data are needed [68,69].

Inflammation and immune modulation — One way in which cancer progresses is through evasion of the host's immune system.

●IL-6 – Interleukin (IL)-6 is a modulatory cytokine, which binds to its corresponding receptor. Elevated levels of these proteins are associated with more aggressive features of bladder cancer (eg, lymphovascular invasion) and advanced stage, as well as higher cancer-specific mortality [70].

●NF-KB – Nuclear factor kappa B (NF-KB) is another transcription factor that is involved in immune regulation and may be dysregulated in bladder cancer [71,72]. NF-KB inhibitor-alpha (NFKBIA), a gene encoding for a member of the NF-KB inhibitor family, was one of the key markers identified by a machine-learning algorithm that could predict recurrence in non-muscle invasive disease at first presentation [73].

●CRP – C-reactive protein (CRP) is an acute-phase protein that, at elevated levels, has been associated with adverse outcomes in bladder cancer [74-79].

●PD-L1 – Programmed cell death ligand 1 (PD-L1) is a T-cell regulatory molecule expressed on tumor and tumor-infiltrating immune cells. It belongs to the class of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. By binding to the associated programmed cell death protein 1 (PD-1), the ligand may prevent tumor cell death by inhibiting the activation of cytotoxic T lymphocytes. (See "Principles of cancer immunotherapy", section on 'PD-1 and PD ligand 1/2'.)

Immune checkpoint inhibitors that block the PD-L1 pathway are commonly used in the management of bladder cancer. Further details are discussed separately (See "Management of recurrent or persistent non-muscle invasive bladder cancer", section on 'Pembrolizumab' and "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder" and "Treatment of metastatic urothelial carcinoma of the bladder and urinary tract".)

Angiogenesis — Factors secreted from tumor cells can interact with endothelial cells in the stroma to establish a vascular supply, thereby providing nutrients to cancer cells. Angiogenesis can be quantified histologically by microvessel density, which has been shown to be prognostic [80]. Microvessel density can add prognostic value in patients with p53-altered tumors [81]. While the prognostic association of microvessel density has not been confirmed by other studies, it has been shown to be increased with nodal metastasis [82,83].

●VEGFs – Vascular endothelial growth factors (VEGFs) are strong angiogenesis-promoting proteins that promote tumor vascularization. VEGF overexpression has been noted in over 80 percent of patients, and has been associated with recurrence, progression, advanced stage, and high-risk features (eg, lymphovascular invasion, nodal metastases, etc) [82,84-89].

●uPA – VEGF induces urokinase-type plasminogen activator (uPA) that degrades extracellular matrix, thereby promoting endothelial migration. Preoperative serum uPA levels have been associated with lymphovascular invasion, nodal metastasis, disease progression, and death from the disease [90].

●TSP-1 – p53 also modulates angiogenesis by upregulating thrombospondin 1 (TSP-1), a strong inhibitor. p53 alterations correlate with TSP-1 underexpression and higher microvessel density [91]. TSP-1 underexpression is associated with poor recurrence-free and overall survival.

Cancer cell invasion — The ability of bladder cancer cells to invade blood vessels and lymphatics determines how well they will be able to metastasize.

●Cadherins – Cadherins are a family of proteins involved in epithelial cell-cell adhesion, of which E-cadherin is a key member. E-cadherin underexpression significantly correlates with tumor recurrence and progression, and poor survival in bladder cancer patients [54,92-95].

●MMPs – Several protease families including uPAs and matrix metalloproteinases (MMPs) can modulate a tumor's ability to disrupt cellular matrix and invade. MMP-2 and MMP-9 overexpression are associated with advanced stage and worse progression free- and overall survival [96-102].

●ICAM1 – Intercellular adhesion molecule 1 (ICAM1) is another mediator of cell adhesion that correlates with grade, size, and nodal status of bladder tumors [103-105].

●CA 19-9 and CEA – Carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) are tumor markers frequently elevated in pancreatic and colon cancer, respectively. Both are involved in cell adhesion. Elevations in these markers predict higher rates of recurrences of bladder cancer, and CA 19-9 elevations have been associated with worse survival in bladder cancer patients after surgery [106,107].

Overall, molecular markers of invasion are therefore reliable predictors of outcomes in bladder cancer.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bladder cancer".)

SUMMARY

●General principles

•The pathogenesis of bladder cancer is influenced by alterations occurring in specific molecular pathways that lead to uncontrolled cellular division. (See 'Pathway-specific molecular alterations' above.)

•Bladder cancer is an entity that cannot be treated solely by pathologic staging; treatment paradigms that incorporate tumor molecular alterations are also necessary. Such analyses may therefore allow for deeper understanding of the pathology of the disease, while identifying biomarkers that can potentially better predict outcomes and therapeutic response. (See 'Molecular subtypes of bladder cancer' above.)

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  83. Jaeger TM, Weidner N, Chew K, et al. Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol 1995; 154:69.
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  86. Zu X, Tang Z, Li Y, et al. Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis. BJU Int 2006; 98:1090.
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  88. Xia G, Kumar SR, Hawes D, et al. Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer. J Urol 2006; 175:1245.
  89. Mitra AP, Almal AA, George B, et al. The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer. BMC Cancer 2006; 6:159.
  90. Shariat SF, Monoski MA, Andrews B, et al. Association of plasma urokinase-type plasminogen activator and its receptor with clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder. Urology 2003; 61:1053.
  91. Grossfeld GD, Ginsberg DA, Stein JP, et al. Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 1997; 89:219.
  92. Mahnken A, Kausch I, Feller AC, Krüger S. E-cadherin immunoreactivity correlates with recurrence and progression of minimally invasive transitional cell carcinomas of the urinary bladder. Oncol Rep 2005; 14:1065.
  93. Mhawech-Fauceglia P, Fischer G, Beck A, et al. Raf1, Aurora-A/STK15 and E-cadherin biomarkers expression in patients with pTa/pT1 urothelial bladder carcinoma; a retrospective TMA study of 246 patients with long-term follow-up. Eur J Surg Oncol 2006; 32:439.
  94. Byrne RR, Shariat SF, Brown R, et al. E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup. J Urol 2001; 165:1473.
  95. Bringuier PP, Umbas R, Schaafsma HE, et al. Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors. Cancer Res 1993; 53:3241.
  96. Davies B, Waxman J, Wasan H, et al. Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion. Cancer Res 1993; 53:5365.
  97. Gerhards S, Jung K, Koenig F, et al. Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma. Urology 2001; 57:675.
  98. Vasala K, Pääkkö P, Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 immunoreactive protein as a prognostic marker in bladder cancer. Urology 2003; 62:952.
  99. Slaton JW, Millikan R, Inoue K, et al. Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy. J Urol 2004; 171:570.
  100. Guan KP, Ye HY, Yan Z, et al. Serum levels of endostatin and matrix metalloproteinase-9 associated with high stage and grade primary transitional cell carcinoma of the bladder. Urology 2003; 61:719.
  101. Szarvas T, Becker M, vom Dorp F, et al. Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer. Cancer Sci 2010; 101:1300.
  102. Szarvas T, Jäger T, Becker M, et al. Validation of circulating MMP-7 level as an independent prognostic marker of poor survival in urinary bladder cancer. Pathol Oncol Res 2011; 17:325.
  103. Roche Y, Pasquier D, Rambeaud JJ, et al. Fibrinogen mediates bladder cancer cell migration in an ICAM-1-dependent pathway. Thromb Haemost 2003; 89:1089.
  104. Ozer G, Altinel M, Kocak B, et al. Potential value of soluble intercellular adhesion molecule-1 in the serum of patients with bladder cancer. Urol Int 2003; 70:167.
  105. Mitra AP, Cote RJ. Molecular signatures that predict nodal metastasis in bladder cancer: does the primary tumor tell tales? Expert Rev Anticancer Ther 2011; 11:849.
  106. Ahmadi H, Djaladat H, Cai J, et al. Precystectomy serum levels of carbohydrate antigen 19-9, carbohydrate antigen 125, and carcinoembryonic antigen: prognostic value in invasive urothelial carcinoma of the bladder. Urol Oncol 2014; 32:648.
  107. Bazargani ST, Clifford T, Djaladat H, et al. Association between epithelial tumor markers' trends during the course of treatment and oncological outcomes in urothelial bladder cancer. Urol Oncol 2017; 35:609.
Topic 118610 Version 9.0

References

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18 : Molecular targets and targeted therapies in bladder cancer management.

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26 : p53 immunohistochemistry as an independent prognostic factor for superficial transitional cell carcinoma of the bladder.

27 : Combined effects of p53, p21, and pRb expression in the progression of bladder transitional cell carcinoma.

28 : p53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer.

29 : p53 predictive value for pT1-2 N0 disease at radical cystectomy.

30 : Cooperative effect of cell-cycle regulators expression on bladder cancer development and biologic aggressiveness.

31 : p53 expression in patients with advanced urothelial cancer of the urinary bladder.

32 : Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer.

33 : p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer.

34 : Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status.

35 : Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer.

36 : Amplification pattern of 12q13-q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer.

37 : Retinoblastoma gene mutations in primary human bladder cancer.

38 : Primary adenocarcinoma of the urinary bladder: value of cell cycle biomarkers.

39 : Decreasing of p27(Kip1)and cyclin E protein levels is associated with progression from superficial into invasive bladder cancer.

40 : Predictive value of combined immunohistochemical markers in patients with pT1 urothelial carcinoma at radical cystectomy.

41 : Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy.

42 : Risk stratification of organ confined bladder cancer after radical cystectomy using cell cycle related biomarkers.

43 : Use of combined apoptosis biomarkers for prediction of bladder cancer recurrence and mortality after radical cystectomy.

44 : Survivin expression is associated with bladder cancer presence, stage, progression, and mortality.

45 : Survivin as a prognostic marker for urothelial carcinoma of the bladder: a multicenter external validation study.

46 : Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53.

47 : BCL2 expression predicts survival in patients receiving synchronous chemoradiotherapy in advanced transitional cell carcinoma of the bladder.

48 : Bcl-2 and p53 expressions in invasive bladder cancers.

49 : Assessing interactions between mdm-2, p53, and bcl-2 as prognostic variables in muscle-invasive bladder cancer treated with neo-adjuvant chemotherapy followed by locoregional surgical treatment.

50 : BCL-2, TP53 and BAX protein expression in superficial urothelial bladder carcinoma.

51 : Immunohistochemical study of pro-apoptotic factors Bax, Fas and CPP32 in urinary bladder cancer: prognostic implications.

52 : Differential expression of bcl-2 family proteins in bladder carcinomas. Relationship with apoptotic rate and survival.

53 : Molecular biology of bladder cancer: prognostic and clinical implications.

54 : Combination of molecular alterations and smoking intensity predicts bladder cancer outcome: a report from the Los Angeles Cancer Surveillance Program.

55 : Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history.

56 : Molecular grade (FGFR3/MIB-1) and EORTC risk scores are predictive in primary non-muscle-invasive bladder cancer.

57 : Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles.

58 : Discovery and validation of novel expression signature for postcystectomy recurrence in high-risk bladder cancer.

59 : Effect of gender on outcomes following radical cystectomy for urothelial carcinoma of the bladder: a critical analysis of 1,994 patients.

60 : Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression.

61 : Expression of estrogen receptors-alpha and -beta in bladder cancer cell lines and human bladder tumor tissue.

62 : Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: A meta-analysis of immunohistochemical studies.

63 : Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer.

64 : Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study.

65 : Generation of a concise gene panel for outcome prediction in urinary bladder cancer.

66 : MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer.

67 : Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer.

68 : Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

69 : Genomic characterization of response to chemoradiation in urothelial bladder cancer.

70 : Preoperative plasma levels of interleukin-6 and its soluble receptor predict disease recurrence and survival of patients with bladder cancer.

71 : Interleukin-6 production by human bladder tumor cell lines is up-regulated by bacillus Calmette-Guérin through nuclear factor-kappaB and Ap-1 via an immediate early pathway.

72 : Insertion/deletion polymorphism in the promoter of NFKB1 as a potential molecular marker for the risk of recurrence in superficial bladder cancer.

73 : Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

74 : Inflammatory biomarkers and bladder cancer prognosis: a systematic review.

75 : The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic infiltration and COX-2 expression and survival in patients with transitional cell carcinoma of the urinary bladder.

76 : Development of a new outcome prediction model in carcinoma invading the bladder based on preoperative serum C-reactive protein and standard pathological risk factors: the TNR-C score.

77 : C-reactive protein level predicts prognosis in patients with muscle-invasive bladder cancer treated with chemoradiotherapy.

78 : Development of a nomogram incorporating serum C-reactive protein level to predict overall survival of patients with advanced urothelial carcinoma and its evaluation by decision curve analysis.

79 : Prognostic risk stratification of patients with urothelial carcinoma of the bladder with recurrence after radical cystectomy.

80 : Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis.

81 : Relationship of tumor angiogenesis and nuclear p53 accumulation in invasive bladder cancer.

82 : Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers.

83 : Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer.

84 : Vascular endothelial growth factor is a predictor of relapse and stage progression in superficial bladder cancer.

85 : Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer.

86 : Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis.

87 : VEGF-C, VEGF-D and Flt-4 in transitional bladder cancer: relationships to clinicopathological parameters and long-term survival.

88 : Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer.

89 : The use of genetic programming in the analysis of quantitative gene expression profiles for identification of nodal status in bladder cancer.

90 : Association of plasma urokinase-type plasminogen activator and its receptor with clinical outcome in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder.

91 : Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression.

92 : E-cadherin immunoreactivity correlates with recurrence and progression of minimally invasive transitional cell carcinomas of the urinary bladder.

93 : Raf1, Aurora-A/STK15 and E-cadherin biomarkers expression in patients with pTa/pT1 urothelial bladder carcinoma; a retrospective TMA study of 246 patients with long-term follow-up.

94 : E-cadherin immunostaining of bladder transitional cell carcinoma, carcinoma in situ and lymph node metastases with long-term followup.

95 : Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors.

96 : Levels of matrix metalloproteases in bladder cancer correlate with tumor grade and invasion.

97 : Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma.

98 : Matrix metalloproteinase-2 immunoreactive protein as a prognostic marker in bladder cancer.

99 : Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy.

100 : Serum levels of endostatin and matrix metalloproteinase-9 associated with high stage and grade primary transitional cell carcinoma of the bladder.

101 : Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer.

102 : Validation of circulating MMP-7 level as an independent prognostic marker of poor survival in urinary bladder cancer.

103 : Fibrinogen mediates bladder cancer cell migration in an ICAM-1-dependent pathway.

104 : Potential value of soluble intercellular adhesion molecule-1 in the serum of patients with bladder cancer.

105 : Molecular signatures that predict nodal metastasis in bladder cancer: does the primary tumor tell tales?

106 : Precystectomy serum levels of carbohydrate antigen 19-9, carbohydrate antigen 125, and carcinoembryonic antigen: prognostic value in invasive urothelial carcinoma of the bladder.

107 : Association between epithelial tumor markers' trends during the course of treatment and oncological outcomes in urothelial bladder cancer

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