Urothelial bladder cancer progression: lessons learned from the bench

Abstract

Urothelial bladder carcinoma (UBC) is an intricate malignancy with a variable natural history and clinical behavior. Despite developments in diagnosis/prognosis refinement and treatment modalities, the recurrence rate is high, and progression from non-muscle to muscle invasive UBC commonly leads to metastasis. Moreover, patients with muscle-invasive or extra-vesical disease often fail the standard chemotherapy treatment, and overall survival rates are poor. Thus, UBC remains a challenge in the oncology field, representing an ideal candidate for research on biomarkers that could identify patients at increased risk of recurrence, progression, and chemo-refractoriness. However, progress toward personalized medicine has been hampered by the unique genetic complexity of UBC. Recent genome-wide expression and sequencing studies have brought new insights into its molecular features, pathogenesis and clinical diversity, revealing a landscape where classical pathology is intersected by the novel and heterogeneous molecular groups. Hence, it seems plausible to postulate that only an integrated signature of prognostic/predictive biomarkers inherent in different cancer hallmarks will reach clinical validation. In this review, we have summarized ours and others’ research into novel putative biomarkers of progression and chemoresistance that encompass several hallmarks of cancer: tumor neovascularization, invasion and metastasis, and energy metabolism reprogramming of the tumor microenvironment.

Keywords

CD147 / lymphovascular invasion / mammalian target of rapamycin / monocarboxylate transporters / progression / Raf kinase inhibitor protein / scoring system / urothelial bladder cancer

References

[1] Apodaca G.The uroepithelium: not just a passive barrier..Traffic2004;5:117-28

[2] Ferlay J,Dikshit R,Mathers C,Parkin DM,Bray F.Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012..Int J Cancer2015;136:E359-86

[3] Reuter VE.The pathology of bladder cancer..Urology2006;67:11-7

[4] Kaufman DS,Feldman AS.Bladder cancer..Lancet2009;374:239-49

[5] Burger M,Dalbagni G,Herr H,Kassouf W,La Vecchia C,Lotan Y.Epidemiology and risk factors of urothelial bladder cancer..Eur Urol2013;63:234-41

[6] van Lingen AV,Witjes JA.Expert review: an update in current and developing intravesical therapies for non-muscle-invasive bladder cancer..Expert Rev Anticancer Ther2013;13:1257-68

[7] Zagouri F,Tzannis K,Bamias A.Current clinical practice guidelines on chemotherapy and radiotherapy for the treatment of non-metastatic muscle-invasive urothelial cancer: a systematic review and critical evaluation by the Hellenic Genito-Urinary Cancer Group (HGUCG)..Crit Rev Oncol Hematol2015;93:36-49

[8] Knowles MA.Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity..Nat Rev Cancer2014;15:25-41

[9] Cheung G,Billia M,Khan MS.Recent advances in the diagnosis and treatment of bladder cancer..BMC Med2013;11:13 PMCID:PMC3566975

[10] Yeung C,Lee J.The health economics of bladder cancer: an updated review of the published literature..Pharmacoeconomics2014;32:1093-104

[11] Babjuk M,Zigeuner R,van Rhijn BW,Sylvester RJ,Bohle A,Roupret M.EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: Update 2013..Eur Urol2013;64:639-53

[12] Witjes JA,Cowan NC,Gakis G,Ribal MJ,Sherif A.EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines..Eur Urol2014;65:778-92

[13] Birkhahn M,Williams AJ,Ye W,Balic M,Steven KE.Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles..Eur Urol2010;57:12-20 PMCID:PMC2828516

[14] van Rhijn BW.Combining molecular and pathologic data to prognosticate non-muscle-invasive bladder cancer..Urol Oncol2012;30:518-23

[15] Ru Y,Theodorescu D.Biomarkers for prognosis and treatment selection in advanced bladder cancer patients..Curr Opin Urol2011;21:420-7 PMCID:PMC3257805

[16] Fuzery AK,Chan MM.Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges..Clin Proteomics2013;10:13 PMCID:PMC3850675

[17] Ye F,Castillo-Martin M,Galsky MD,Boffetta P,Cordon-Cardo C.Biomarkers for bladder cancer management: present and future..Am J Clin Exp Urol2014;2:1-14

[18] Miremami J.The promise of novel molecular markers in bladder cancer..Int J Mol Sci2014;15:23897-908 PMCID:PMC4284796

[19] Buti S,Zanoni D,Modena A,Gilli A,Brunelli M,Cascinu S,Tortora G.Prognostic and predictive factors in patients treated with chemotherapy for advanced urothelial cancer: where do we stand?.Future Oncol2015;11:107-19

[20] Soloway MS.Bladder cancer: Lack of progress in bladder cancer -what are the obstacles?.Nat Rev Urol2013;10:5-6

[21] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[22] Mendoza M.Revisiting the seed and soil in cancer metastasis..Int J Biochem Cell Biol2009;41:1452-62

[23] Leber MF.Molecular principles of cancer invasion and metastasis (review)..Int J Oncol2009;34:881-95

[24] Ferris RL,Leong SP,Morton DL.Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread..Clin Exp Metastasis2012;29:729-36 PMCID:PMC3485421

[25] Pereira ER,Jung K.The lymph node microenvironment and its role in the progression of metastatic cancer..Semin Cell Dev Biol2015;38:98-105 PMCID:PMC4397158

[26] Seyfried TN.On the origin of cancer metastasis..Crit Rev Oncog2013;18:43-73

[27] Holopainen T,Alitalo K.Perspectives on lymphangiogenesis and angiogenesis in cancer..J Surg Oncol2011;103:484-8

[28] Cao Z,Zhang G,Sarkar FH,Zhou Q.Tumor cell-mediated neovascularization and lymphangiogenesis contrive tumor progression and cancer metastasis..Biochim Biophys Acta2013;1836:273-86

[29] Shibata MA,Shibata E.Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model..Cancer Gene Ther2008;15:776-86

[30] Zhang D,Shi J,Zhang X,Hou S,Kou G,Guo Y.Suppression of tumor growth and metastasis by simultaneously blocking vascular endothelial growth factor (VEGF)-A and VEGF-C with a receptor-immunoglobulin fusion protein..Cancer Res2010;70:2495-503

[31] Eklund L,Alitalo K.Mouse models for studying angiogenesis and lymphangiogenesis in cancer..Mol Oncol2013;7:259-82 PMCID:PMC5528409

[32] Gacche RN.Angiogenic factors as potential drug target: efficacy and limitations of anti-angiogenic therapy..Biochim Biophys Acta2014;1846:161-79

[33] Kim S,Zhang L,Chen S.Clinical response to sunitinib as a multitargeted tyrosine-kinase inhibitor (TKI) in solid cancers: a review of clinical trials..Onco Targets Ther2014;7:719-28

[34] Welti J,Dimmeler S.Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer..J Clin Invest2013;123:3190-200 PMCID:PMC3726176

[35] Maione F.Tumor angiogenesis: methods to analyze tumor vasculature and vessel normalization in mouse models of cancer..Methods Mol Biol2015;1267:349-65

[36] Pignot G,Vacher S,Vieillefond A,Lidereau R.Large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker..Eur Urol2009;56:678-88

[37] Santos L,Pereira S,Amaro T,Guimaraes T,Lobo F,Lopes C.Neovascularisation is a prognostic factor of early recurrence in T1/G2 urothelial bladder tumours..Ann Oncol2003;14:1419-24

[38] Canoglu A,Beduk Y,Tulunay O.Microvessel density as a prognostic marker in bladder carcinoma: correlation with tumor grade, stage and prognosis..Int Urol Nephrol2004;36:401-5

[39] Fauconnet S,Lascombe I,Clairotte A,Chabannes E.Expression analysis of VEGF-A and VEGF-B: relationship with clinicopathological parameters in bladder cancer..Oncol Rep2009;21:1495-504

[40] Afonso J,Longatto-Filho A.Canda A.Bladder cancer - From basic science to robotic surgery..Angiogenesis, Lymphangiogenesis and Lymphovascular Invasion: Prognostic Impact for Bladder Cancer Patients.2012;CroatiaINTECH87-116

[41] Ghosh M,Agarwal PK.Targeted therapies in urothelial carcinoma..Curr Opin Oncol2014;26:305-20

[42] von Hardenberg J,Knauer A,Becker A,Schubert C,Bolenz C.Expression and predictive value of lymph-specific markers in urothelial carcinoma of the bladder..Urol Oncol2014;32:54.e9-17

[43] Zu X,Li Y,Ding J.Vascular endothelial growth factor-C expression in bladder transitional cell cancer and its relationship to lymph node metastasis..BJU Int2006;98:1090-3

[44] Fernandez-Gomez J,Unda M,Gonzalez M,Madero R,Pertusa C,Camacho JE,Rabadan M,Montesinos M,Gimeno A,Martinez-Pineiro JA.Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials..Eur Urol2008;53:992-1001

[45] Zhou M,Zu X,Zeng H.Lymphatic vessel density as a predictor of lymph node metastasis and its relationship with prognosis in urothelial carcinoma of the bladder..BJU Int2011;107:1930-5

[46] Yang H,Kim MJ,Alitalo K,Kim I,Koh GY.Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer..Mol Cancer2011;10:36 PMCID:PMC3080348

[47] Zhang HH,Shi YR,Zhou M,Chen MF,Zu XB.RNA interference-mediated vascular endothelial growth factor-C reduction suppresses malignant progression and enhances mitomycin C sensitivity of bladder cancer T24 cells..Cancer Biother Radiopharm2012;27:291-8

[48] Shariat SF,Tilki D,Karakiewicz PI,Bastian PJ,Kassouf W,Fritsche HM,Ficarra V,Sagalowsky AI,Kamat AM,Lotan Y,Fradet Y.International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy..BJU Int2010;105:1402-12

[49] von Rundstedt FC,Groshen S,Skinner DG,Cote RJ,Godoy G.Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial..BJU Int2014;

[50] Martin-Doyle W,Orsola A,Bellmunt J.Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients..J Clin Oncol2015;33:643-50

[51] Bolenz C,Bastian PJ,Wulfing C,Buchner A,Fritsche HM,Wieland WF,Haferkamp A,Muller SC,Trojan L.Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node-negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial..BJU Int2010;106:493-9

[52] Algaba F.Lymphovascular invasion as a prognostic tool for advanced bladder cancer..Curr Opin Urol2006;16:367-71

[53] Mazzucchelli R,Lopez-Beltran A,Montironi R.Clinicopathological significance of lymphovascular invasion in urothelial carcinoma..Anal Quant Cytol Histol2012;34:173-9

[54] Afonso J,Amaro T,Longatto-Filho A.The aggressiveness of urothelial carcinoma depends to a large extent on lymphovascular invasion --the prognostic contribution of related molecular markers..Histopathology2009;55:514-24

[55] Chaudhary R,Clarke NW,Barnard RJ,Kumar S.Prognostic relevance of micro-vessel density in cancer of the urinary bladder..Anticancer Res1999;19:3479-84

[56] Shariat SF,Gupta A,Karakiewicz PI,Jeldres C,Ashfaq R.Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers..J Urol2010;183:1744-50

[57] Rink M,Green D,Robinson BD,Sagalowsky AI,Karakiewicz PI,Scherr DS.Biomolecular predictors of urothelial cancer behavior and treatment outcomes..Curr Urol Rep2012;13:122-35

[58] Horikawa Y,Narita S,Yuasa T,Nanjo H,Tsuchiya N.Lymphatic invasion is a prognostic factor for bladder cancer treated with radical cystectomy..Int J Clin Oncol2007;12:131-6

[59] Ma Y,Liu B,Yang S.Intratumoral lymphatics and lymphatic vessel invasion detected by D2-40 are essential for lymph node metastasis in bladder transitional cell carcinoma..Anat Rec (Hoboken).2010;293:1847-54

[60] Padera TP,di Tomaso E,Brown EB,Choi NC,Wain J,Munn LL.Lymphatic metastasis in the absence of functional intratumor lymphatics..Science2002;296:1883-6

[61] Padera TP,Tooredman JB,di Tomaso E.Pathology: cancer cells compress intratumour vessels..Nature2004;427:695

[62] Bolenz C,Strobel P,Schubert C.The lymphatic system in clinically localized urothelial carcinoma of the bladder: morphologic characteristics and predictive value..Urol Oncol2013;31:1606-14

[63] De Bock K,Carmeliet P.Vessel abnormalization: Another hallmark of cancer? Molecular mechanisms and therapeutic implications..Curr Opin Genet Dev2011;21:73-9

[64] Bambury RM.Advanced urothelial carcinoma: overcoming treatment resistance through novel treatment approaches..Front Pharmacol2013;4:3

[65] Carmeliet P.Molecular mechanisms and clinical applications of angiogenesis..Nature2011;473:298-307 PMCID:PMC4049445

[66] Videira PA,Cabral MG,Correia M,Gouveia H,Almeida JF,Santos LL.Effects of bevacizumab on autocrine VEGF stimulation in bladder cancer cell lines..Urol Int2011;86:95-101

[67] Humar R,Berns H,Battegay EJ.Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling..FASEB J2002;16:771-80

[68] Watanabe R,Huang J.mTOR signaling, function, novel inhibitors, and therapeutic targets..J Nucl Med2011;52:497-500

[69] Fechner G,Schmidt D,Muller SC.Rapamycin inhibits in vitro growth and release of angiogenetic factors in human bladder cancer..Urology2009;73:665-8

[70] Seront E,Sautois B,D'Hondt LA,Canon JL,Vandenbulcke JM,Goeminne JC,Verhoeven D,Branders S,Schoonjans J,Machiels JP.Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers..Ann Oncol2012;23:2663-70

[71] Houede N.Targeting the genetic alterations of the PI3K-AKT-mTOR pathway: its potential use in the treatment of bladder cancers..Pharmacol Ther2015;145:1-18

[72] Carneiro BA,Kuzel TM,Abdulkadir SA.Emerging therapeutic targets in bladder cancer..Cancer Treat Rev2015;41:170-8

[73] Sun CH,Pan CC.Activation of the PI3K/Akt/ mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder..Histopathology2011;58:1054-63

[74] Schultz L,Hicks J,DeMarzo AM,Nielsen ME,Sidransky D,Netto GJ.Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy..Cancer2010;116:5517-26 PMCID:PMC3568488

[75] Afonso J,DA Silva VM,Santos LL.Phospho-mTOR in non-tumour and tumour bladder urothelium: pattern of expression and impact on urothelial bladder cancer patients..Oncol Lett2014;8:1447-454 PMCID:PMC4156165

[76] cancer Genome Atlas Research Network..Comprehensive molecular characterization of urothelial bladder carcinoma..Nature2014;507:315-22 PMCID:PMC3962515

[77] Chaffer CL.A perspective on cancer cell metastasis..Science2011;331:1559-64

[78] Hurst DR.Metastasis suppressor genes at the interface between the environment and tumor cell growth..Int Rev Cell Mol Biol2011;286:107-80

[79] Liu W,Brinker AE,Lianidou E.Microenvironmental Influences on Metastasis Suppressor Expression and Function during a Metastatic Cell's Journey..Cancer Microenviron2014;7:117-31 PMCID:PMC4275500

[80] Al-Mulla F,Taqi Z.RKIP: Much more than Raf kinase inhibitory protein..J Cell Physiol2013;228:1688-702

[81] Yesilkanal AE.Raf kinase inhibitory protein (RKIP) as a metastasis suppressor: regulation of signaling networks in cancer..Crit Rev Oncog2014;19:447-54

[82] Escara-Wilke J,Keller ET.Raf kinase inhibitor protein (RKIP) in cancer..Cancer Metastasis Rev2012;31:615-20

[83] Lamiman K,Mizokami A,Keller ET.Survey of Raf kinase inhibitor protein (RKIP) in multiple cancer types..Crit Rev Oncog2014;19:455-68

[84] Zaravinos A,Lambrou GI,Delakas D.Implication of RAF and RKIP genes in urinary bladder cancer..Pathol Oncol Res2011;17:181-90

[85] Afonso J,Martinho O,Amaro T,Santos LL.Low RKIP expression associates with poor prognosis in bladder cancer patients..Virchows Arch2013;462:445-53

[86] Bonavida B,Vega MI,Baritaki S.Roles Each of Snail, Yin Yang 1 and RKIP in the Regulation of Tumor Cells Chemo-immuno-resistance to Apoptosis..For Immunopathol Dis Therap2013;4:79-92 PMCID:PMC3811117

[87] Bonavida B.RKIP-mediated chemo-immunosensitization of resistant cancer cells via disruption of the NF-kappaB/ Snail/YY1/RKIP resistance-driver loop..Crit Rev Oncog2014;19:431-45 PMCID:PMC4299472

[88] Phan LM,Lee MH.Cancer metabolic reprogramming: Importance, main features, and potentials for precise targeted anti-cancer therapies..Cancer Biol Med2014;11:1-19

[89] Warburg O.On the origin of cancer cells..Science1956;123:309-14

[90] Doherty JR.Targeting lactate metabolism for cancer therapeutics..J Clin Invest2013;123:3685-92 PMCID:PMC3754272

[91] Munoz-Pinedo C,Ricci JE.Cancer metabolism: current perspectives and future directions..Cell Death Dis2012;3:E248

[92] Upadhyay M,Kandpal M,Vivekanandan P.The Warburg effect: Insights from the past decade..Pharmacol Ther2013;137:318-30

[93] Halestrap AP.The SLC16 gene family - Structure, role and regulation in health and disease..Mol Aspects Med2013;34:337-49

[94] Kirk P,Heddle C,Barclay AN.CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression..EMBO J2000;19:3896-904 PMCID:PMC306613

[95] Xiong L,Zhou L.The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature..Int J Mol Sci2014;15:17411-41 PMCID:PMC4227170

[96] Baltazar F,Morais-Santos F,Queiros O,Casal M.Monocarboxylate transporters as targets and mediators in cancer therapy response..Histol Histopathol2014;29:1511-24

[97] Zhu C,He B,Xu Y,Bao Q,Wang S.Inhibition of CD147 gene expression via RNA interference reduces tumor cell invasion, tumorigenicity and increases chemosensitivity to cisplatin in laryngeal carcinoma Hep2 cells..Oncol Rep2011;25:425-32

[98] Zeng HZ,Liang AB,Zhang WJ,Wang H.Expression of CD147 in advanced non-small cell lung cancer correlated with cisplatin-based chemotherapy resistance..Neoplasma2011;58:449-54

[99] Huang Z,Wang Y,Li H,Chen W.Overexpression of CD147 contributes to the chemoresistance of head and neck squamous cell carcinoma cells..J Oral Pathol Med2013;42:541-6

[100] Afonso J,Miranda-Goncalves V,Amaro T,Baltazar F.CD147 and MCT1-potential partners in bladder cancer aggressiveness and cisplatin resistance..Mol Carcinog2014;

[101] Afonso J,Baltazar F,Costa FE,Amaro T,Santos LL.CD147 overexpression allows an accurate discrimination of bladder cancer patients' prognosis..Eur J Surg Oncol2011;37:811-7

[102] Deora AA,Hu J,Rodriguez-Boulan E.Mechanisms regulating tissue-specific polarity of monocarboxylate transporters and their chaperone CD147 in kidney and retinal epithelia..Proc Natl Acad Sci U S A2005;102:16245-50 PMCID:PMC1283422

[103] Xue YJ,Sun ZX.CD147 overexpression is a prognostic factor and a potential therapeutic target in bladder cancer..Med Oncol2011;28:1363-72

[104] Als AB,von der Maase H,Mansilla F,Jensen JL,Sengelov L,Orntoft TF.Emmprin and survivin predict response and survival following cisplatin-containing chemotherapy in patients with advanced bladder cancer..Clin Cancer Res2007;13:4407-14

[105] Takata R,Kanehira M,Shuin T,Namiki M,Matsushita Y,Nakamura Y.Predicting response to methotrexate, vinblastine, doxorubicin, and cisplatin neoadjuvant chemotherapy for bladder cancers through genome-wide gene expression profiling..Clin Cancer Res2005;11:2625-36

[106] Choi JW,Lee JH.Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder..Urology2014;84:245.e9-15

[107] Tang X,Xu L,Mi M.CD147/EMMPRIN: an effective therapeutic target for hepatocellular carcinoma..J Drug Target2013;21:224-31

[108] Choi W,Ochoa A,Siefker-Radtke A,McConkey DJ.Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer..Nat Rev Urol2014;11:400-10

[109] Sylvester RJ,Oosterlinck W,Bouffioux C,Newling DW.Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials..Eur Urol2006;49:466-5

[110] Fernandez-Gomez J,Solsona E,Martinez-Pineiro L,Portillo J,Pertusa C,Camacho JE,Astobieta A,Isorna S,Gimeno A,Martinez-Pineiro JA.Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: The CUETO scoring model..J Urol2009;182:2195-203

[111] Karakiewicz PI,Palapattu GS,Lotan Y,Vazina A,Bastian PJ,Sagalowsky AI,Lerner SP.Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder..J Urol2006;176:1354-61

[112] Shariat SF,Palapattu GS,Lotan Y,Vazina A,Gupta A,Schoenberg M.Nomograms provide improved accuracy for predicting survival after radical cystectomy..Clin Cancer Res2006;12:6663-76

[113] Bassi P,De Marco V,Volpe A.Prognostic accuracy of an artificial neural network in patients undergoing radical cystectomy for bladder cancer: a comparison with logistic regression analysis..BJU Int2007;99:1007-12

[114] Buchner A,Burger M,Herrmann E,Ellinger J,Nuhn P,Brookman-May S,Peter J,Tilki D,Roigas J,Hohenfellner M,Trojan L,Muller SC,Bastian PJ.Prediction of outcome in patients with urothelial carcinoma of the bladder following radical cystectomy using artificial neural networks..Eur J Surg Oncol2013;39:372-9

[115] Shariat SF,Lotan Y,Karakiewicz PI.Nomograms for bladder cancer..Eur Urol2008;54:41-53

[116] Shariat SF,Godoy G.Use of nomograms for predictions of outcome in patients with advanced bladder cancer..Ther Adv Urol2009;1:13-26 PMCID:PMC3126044

[117] Shariat SF,Ashfaq R,Palapattu GS,Sagalowsky AI.Multiple biomarkers improve prediction of bladder cancer recurrence and mortality in patients undergoing cystectomy..Cancer2008;112:315-25

[118] Bryan RT,James ND,Cheng KK.Biomarkers in bladder cancer..BJU Int2010;105:608-13

[119] Shariat SF,Karakiewicz PI,Isbarn H,Bastian PJ,Capitanio U,Montorsi F,Sagalowsky AI,Lotan Y.Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer..J Urol2010;183:68-75

[120] Lotan Y,Passoni N,Kapur P,Bolenz C,Raj GV,Shariat SF.Prospective Evaluation of a Molecular Marker Panel for Prediction of Recurrence and Cancer-specific Survival After Radical Cystectomy..Eur Urol2013;64:465-71

[121] Damrauer JS,Chism DD,Tiganelli CJ,Yeh JJ,Iyer G,Kim WY.Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology..Proc Natl Acad Sci U S A2014;111:3110-5 PMCID:PMC3939870

[122] Choi W,Kim S,Plimack ER,Roth B,Tran M,Melquist J,Majewski T,Pretzsch S,Siefker-Radtke A,Dinney CP.Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy..Cancer Cell2014;25:152-65 PMCID:PMC4011497

[123] Brücher BL,van Hillegersberg R,Lordick F,Ushijima T,Skricka T,Wallner G,Garofalo A,Roviello F,Wallace TJ,Maihle N,Ducreux M,Knuth A,Steele SR.Imagine a world without cancer..BMC Cancer2014;14:186 PMCID:PMC3995593