Bladder cancer, one of the most frequently occurring human cancers, develops via two tracks referred to as papillary and nonpapillary that correspond to clinically different forms of the disease. Most bladder cancers are chemically induced, with tobacco smoking being the leading risk factor. Recent advances in bladder cancer research have enhanced our understanding of the origin of this disease from urothelial progenitor cells via field effects along papillary/luminal and nonpapillary/basal pathways. Evident from the outset of the disease, the diversity of the luminal and basal pathways, together with cell lineage tracing studies, postulates the origin of molecularly distinct subtypes from different uroprogenitor cells. The molecular mechanisms initiating field effects involve a new class of genes referred to as forerunner (FR) genes that generally map around major tumor suppressors such as RB1. These genes are silenced, predominantly by hypermethylation and less frequently by mutations, and drive the expansion of intraurothelial preneoplastic cells. Different FR genes are involved in various molecular subtypes of bladder cancer and they sensitize the uroprogenitor cells to the development of luminal and basal bladder cancers in animal models. In human bladder cancer, luminal and basal forms have dissimilar clinical behavior and response to conventional and targeted chemotherapeutic manipulations. These new research developments hold the promise of expanding our armamentarium of diagnostic and treatment options for patients with bladder cancer and improving our ability to select patients most likely to respond to a specific therapy.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Siegel R, Ma J, Zou Z, Jemal A. 1.  2014. Cancer statistics. CA Cancer J. Clin. 64:9–29 [Google Scholar]
  2. Chavan S, Bray F, Lortet-Tieulent J, Goodman M, Jemal A. 2.  2014. International variations in bladder cancer incidence and mortality. Eur. Urol. 66:59–73 [Google Scholar]
  3. Barsoum RS. 3.  2013. Urinary schistosomiasis: review. J. Adv. Res. 4:453–59 [Google Scholar]
  4. Zaghloul MS. 4.  2012. Bladder cancer and schistosomiasis. J. Egypt. Natl. Cancer Inst. 24:151–59 [Google Scholar]
  5. Zaghloul MS, Gouda I. 5.  2012. Schistosomiasis and bladder cancer: similarities and differences from urothelial cancer. Expert Rev. Anticancer Ther. 12:753–63 [Google Scholar]
  6. Behrens T, Pesch B, Bruning T. 6.  2012. Urinary bladder cancer risk factors in Egypt. Cancer Epidemiol. Biomark. Prev. 21:693 [Google Scholar]
  7. Jiang X, Castelao JE, Yuan JM, Stern MC, Conti DV. 7.  et al. 2012. Cigarette smoking and subtypes of bladder cancer. Int. J. Cancer 130:896–901 [Google Scholar]
  8. Porru S, Scotto di Carlo A, Carta A, Placidi D. 8.  2003. Bladder cancer and occupational activity. G. Ital. Med. Lav. Ergon. 25:298–300 [Google Scholar]
  9. Carreon T, LeMasters GK, Ruder AM, Schulte PA. 9.  2006. The genetic and environmental factors involved in benzidine metabolism and bladder carcinogenesis in exposed workers. Front. Biosci. 11:2889–902 [Google Scholar]
  10. Ayala AG, Ro JY, Amin M. 10.  2001. Pathology of Incipient Neoplasia. New York: Oxford Univ. Press [Google Scholar]
  11. Dinney C, McConkey DJ, Millikan RE, Wu X, Bar-Eli M. 11.  et al. 2004. Focus on bladder cancer. Cancer Cell 6:111–16 [Google Scholar]
  12. Spiess PE, Czerniak B. 12.  2006. Dual-track pathway of bladder carcinogenesis: practical implications. Arch. Pathol. Lab. Med. 130:844–52 [Google Scholar]
  13. Koss LG. 13.  1979. Mapping of the urinary bladder: its impact on the concepts of bladder cancer. Hum. Pathol. 10:533–48 [Google Scholar]
  14. Koss LG, Nakanishi I, Freed SZ. 14.  1977. Nonpapillary carcinoma in situ and atypical hyperplasia in cancerous bladders: further studies of surgically removed bladders by mapping. Urology 9:442–55 [Google Scholar]
  15. Koss LG, Tiamson EM, Robbins MA. 15.  1974. Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. JAMA 227:281–86 [Google Scholar]
  16. Van Batavia J, Yamany T, Molotkov A, Dan H, Mansukhani M. 16.  et al. 2014. Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 16:10982–91 [Google Scholar]
  17. Shin K, Lim A, Odegaard JI, Honeycutt JD, Kawano S. 17.  et al. 2014. Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma. Nat. Cell Biol. 16:5469–78 [Google Scholar]
  18. Shin K, Lim A, Zhao C, Sahoo D, Pan Y. 18.  et al. 2014. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26:4521–33 [Google Scholar]
  19. Sonpavde G, Stemberg CN, Rosenberg JE, Hahn NM, Galsky MD. 19.  et al. 2010. Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol. 11:9861–70 [Google Scholar]
  20. Lindgren D, Frigyesi A, Gudjonsson S, Sjodahl G, Hallden C. 20.  et al. 2010. Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res. 70:93463–72 [Google Scholar]
  21. Gui Y, Guo G, Huang Y, Hu X, Tang A. 21.  et al. 2011. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43:875–78 [Google Scholar]
  22. 22. Cancer Genome Atlas Research Network 2014. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:7492315–22 [Google Scholar]
  23. Iyer G, Al-Ahmadie H, Schultz N, Hanrahan AJ, Ostrovnaya I. 23.  et al. 2013. Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J. Clin. Oncol. 31:253133–40 [Google Scholar]
  24. Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S. 24.  et al. 2012. A molecular taxonomy for urothelial carcinoma. Clin. Cancer Res. 18:123377–86 [Google Scholar]
  25. Choi W, Porten S, Kim S, Willis D, Plimack ER. 25.  et al. 2014. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:2152–65 [Google Scholar]
  26. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ. 26.  et al. 2014. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. PNAS 111:83110–15 [Google Scholar]
  27. Choi W, Czerniak B, Ochoa A, Su X, Siefker-Radtke A. 27.  et al. 2014. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat. Rev. Urol. 11:7400–10 [Google Scholar]
  28. McConkey DJ, Choi W, Dinney CP. 28.  2014. New insights into subtypes of invasive bladder cancer: considerations of the clinician. Eur. Urol. 66:4609–10 [Google Scholar]
  29. Powles T. Vogelzang NJ, Fine GD, Eder JP, Braiteh FS. 29.  et al. 2014. Inhibition of PD-L1 by MPDL3280A and clinical activity in patients with metastatic urothelial bladder cancer (UBC). J. Clin. Oncol. 32:Suppl.5s (Abstr. 5011) [Google Scholar]
  30. Dinney CP, Hansel D, McConkey D, Shipley W, Hagan W. 30.  et al. 2014. Novel neoadjuvant paradigms for bladder cancer research: results from the National Cancer Center Institute Forum. Urol. Oncol. 32:81108–15 [Google Scholar]
  31. Letašiová S, Medved'ová A, Šovčíková A, Dušinská M, Volkovová K. 31.  et al. 2012. Bladder cancer, a review of the environmental risk factors. Environ. Health 11:Suppl. 1S11 [Google Scholar]
  32. Silverman DT, Devesa SS, Moore LE, Rothman N. 32.  2006. Bladder cancer. Cancer Epidemiology and Prevention D Schottenfeld, JF Fraumeni 1101–27 New York: Oxford Univ. Press [Google Scholar]
  33. Andrew AS, Schned AR, Heaney JA, Karagas MR. 33.  2004. Bladder cancer risk and personal hair dye use. Int. J. Cancer 109:581–86 [Google Scholar]
  34. Jankovic S, Radosavljevic V. 34.  2007. Risk factors for bladder cancer. Tumori 93:4–12 [Google Scholar]
  35. Catsburg CE, Gago-Dominguez M, Yuan JM, Castelao JE, Cortessis VK. 35.  et al. 2014. Dietary sources of N-nitroso compounds and bladder cancer risk: findings from the Los Angeles bladder cancer study. Int. J. Cancer 134:125–35 [Google Scholar]
  36. Kantor AF, Hartge P, Hoover RN, Fraumeni JF. 36.  1985. Familial and environmental interactions in bladder cancer risk. Int. J. Cancer 35:703–6 [Google Scholar]
  37. Murta-Nascimento C, Silverman DT, Kogevinas M, García-Closas M, Rothman N. 37.  et al. 2007. Risk of bladder cancer associated with family history of cancer: Do low-penetrance polymorphisms account for the increase in risk?. Cancer Epidemiol. Biomark. Prev. 16:1595–600 [Google Scholar]
  38. Aben KK, Baglietto L, Baffoe-Bonnie A, Coebergh JW, Bailey-Wilson JE. 38.  et al. 2006. Segregation analysis of urothelial cell carcinoma. Eur. J. Cancer 42:1428–33 [Google Scholar]
  39. Kiemeney LA, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson A. 39.  et al. 2010. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat. Genet. 42:415–19 [Google Scholar]
  40. Kiemeney LA, Thorlacius S, Sulem P, Geller F, Aben KK. 40.  et al. 2008. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat. Genet. 40:1307–12 [Google Scholar]
  41. Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T. 41.  et al. 2009. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41:991–95 [Google Scholar]
  42. Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X. 42.  et al. 2010. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat. Genet. 42:978–84 [Google Scholar]
  43. Eeles RA, Kote-Jarai Z, Al Olama AA, Giles GG, Guy M. 43.  et al. 2009. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat. Genet. 41:1116–21 [Google Scholar]
  44. Yeager M, Chatterjee N, Ciampa J, Jacobs KB, Gonzalez-Bosquet J. 44.  et al. 2009. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat. Genet. 41:1055–57 [Google Scholar]
  45. Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M. 45.  et al. 2010. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42:132–36 [Google Scholar]
  46. Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K. 46.  et al. 2008. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat. Genet. 40:623–30 [Google Scholar]
  47. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D. 47.  et al. 2007. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447:1087–93 [Google Scholar]
  48. Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A. 48.  et al. 2007. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat. Genet. 39:989–94 [Google Scholar]
  49. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P. 49.  et al. 2007. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39:645–49 [Google Scholar]
  50. Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J. 50.  et al. 2009. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41:221–27 [Google Scholar]
  51. Stacey SN, Sulem P, Masson G, Gudjonsson SA, Thorleifsson G. 51.  et al. 2009. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41:909–14 [Google Scholar]
  52. Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM. 52.  et al. 2009. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am. J. Hum. Genet. 85:679–91 [Google Scholar]
  53. Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M. 53.  et al. 2009. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41:899–904 [Google Scholar]
  54. Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ. 54.  et al. 2010. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat. Genet. 42:224–28 [Google Scholar]
  55. Fu YP, Kohaar I, Moore LE, Lenz P, Figueroa JD. 55.  et al. 2014. The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease. Cancer Res. 74:5808–18 [Google Scholar]
  56. Bell DA, Taylor JA, Paulson DF, Robertson CN, Mohler JL. 56.  et al. 1993. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J. Natl. Cancer Inst. 85:1159–64 [Google Scholar]
  57. Golka K, Reckwitz T, Kempkes M, Cascorbi II, Blaskewicz M. 57.  et al. 1997. N-acetyltransferase 2 (NAT2) and glutathione S-transferase μ (GSTM1) in bladder cancer patients in a highly industrialized area. Int. J. Occup. Environ. Health 3:105–10 [Google Scholar]
  58. García-Closas M, Malats N, Silverman D, Dosemeci M, Kogevinas M. 58.  et al. 2005. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 366:649–59 [Google Scholar]
  59. Zhang ZT, Pak J, Huang HY, Shapiro E, Sun TT. 59.  et al. 2001. Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20:1973–80 [Google Scholar]
  60. Mo L, Zheng X, Huang HY, Shapiro E, Lepor H. 60.  et al. 2007. Hyperactivation of Ha-ras oncogene, but no Ink4a/Arf deficiency, triggers bladder tumorigenesis. J. Clin. Investig. 117:314–25 [Google Scholar]
  61. Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR. 61.  et al. 1999. Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res. 59:3512–17 [Google Scholar]
  62. Cheng J, Huang H, Pak J, Shapiro E, Sun TT. 62.  et al. 2003. Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder. Cancer Res. 63:179–85 [Google Scholar]
  63. Gao J, Huang HY, Pak J, Cheng J, Zhang ZT. 63.  et al. 2004. p53 deficiency provokes urothelial proliferation and synergizes with activated Ha-ras in promoting urothelial tumorigenesis. Oncogene 23:687–96 [Google Scholar]
  64. Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH. 64.  et al. 2009. Inactivation of p53 and PTEN promotes invasive bladder cancer. Genes Dev. 23:675–80 [Google Scholar]
  65. Czerniak B, Cohen GL, Etkind P, Deitch D, Simmons H. 65.  et al. 1992. Concurrent mutations of coding and regulatory sequences of the Ha-ras gene in urinary bladder carcinomas. Hum. Pathol. 23:1199–204 [Google Scholar]
  66. Knowles MA, Williamson M. 66.  1993. Mutation of H-ras is infrequent in bladder cancer: confirmation by single-strand conformation polymorphism analysis, designed restriction fragment length polymorphisms, and direct sequencing. Cancer Res. 53:133–39 [Google Scholar]
  67. Karimianpour N, Mousavi-Shafaei P, Ziaee AA, Akbari MT, Pourmand G. 67.  et al. 2008. Mutations of RAS gene family in specimens of bladder cancer. Urol. J. 5:237–42 [Google Scholar]
  68. Sibley K, Cuthbert-Heavens D, Knowles MA. 68.  2001. Loss of heterozygosity at 4p16.3 and mutation of FGFR3 in transitional cell carcinoma. Oncogene 20:686–91 [Google Scholar]
  69. Sibley K, Stern P, Knowles MA. 69.  2001. Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours. Oncogene 20:4416–18 [Google Scholar]
  70. Knowles MA. 70.  2007. Role of FGFR3 in urothelial cell carcinoma: biomarker and potential therapeutic target. World J. Urol. 25:581–93 [Google Scholar]
  71. Tomlinson DC, Hurst CD, Knowles MA. 71.  2007. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene 26:5889–99 [Google Scholar]
  72. Qing J, Du X, Chen Y, Chan P, Li H. 72.  et al. 2009. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J. Clin. Investig. 119:1216–29 [Google Scholar]
  73. Esrig D, Elmajian D, Groshen S, Freeman JA, Stein JP. 73.  et al. 1994. Accumulation of nuclear p53 and tumor progression in bladder cancer. N. Engl. J. Med. 331:1259–64 [Google Scholar]
  74. Esrig D, Spruck CH III, Nichols PW, Chaiwun B, Steven K. 74.  et al. 1993. p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am. J. Pathol. 143:1389–97 [Google Scholar]
  75. Chatterjee SJ, Datar R, Youssefzadeh D, George B, Goebell PJ. 75.  et al. 2004. Combined effects of p53, p21, and pRB expression in the progression of bladder transitional cell carcinoma. J. Clin. Oncol. 22:1007–13 [Google Scholar]
  76. Shariat SF, Bolenz C, Karakiewicz PI, Fradet Y, Ashfaq R. 76.  et al. 2010. P53 expression in patients with advanced urothelial cancer of the urinary bladder. Br. J. Urol. Int. 105:489–95 [Google Scholar]
  77. Shariat SF, Lotan Y, Karakiewicz PI, Ashfaq R, Isbam H. 77.  et al. 2009. p53 predictive value for pT1-2 N0 disease at radical cystectomy. J. Urol. 182:907–13 [Google Scholar]
  78. Cote RJ, Dunn MD, Chatterjee SJ, Stein JP, Shi SR. 78.  et al. 1998. Elevated and absent pRB expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res. 48:1090–94 [Google Scholar]
  79. Teng DH, Hu R, Lin H, Davis T, Iliev D. 79.  et al. 1997. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 57:5221–55 [Google Scholar]
  80. Aveyard JS, Skilleter A, Habuchi T, Knowles MA. 80.  et al. 1999. Somatic mutation of PTEN in bladder carcinoma. Br. J. Cancer 80:904–8 [Google Scholar]
  81. Wang DS, Rieger-Christ K, Latini JM, Moinzadeh A, Stoffel J. 81.  et al. 2000. Molecular analysis of PTEN and MXI1 in primary bladder carcinoma. Int. J. Cancer 88:620–25 [Google Scholar]
  82. Harris LD, De La Cerda J, Tuziak T, Rosen D, Xiao L. 82.  et al. 2008. Analysis of the expression of biomarkers in urinary bladder cancer using a tissue microarray. Mol. Carcinog. 47:678–85 [Google Scholar]
  83. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB. 83.  et al. 2007. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. PNAS 104:7564–69 [Google Scholar]
  84. Gildea JJ, Herlevsen M, Harding MA, Gulding KM, Moskaluk CA. 84.  et al. 2004. PTEN can inhibit in vitro organotypic and in vivo orthotopic invasion of human bladder cancer cells even in the absence of its lipid phosphatase activity. Oncogene 23:6788–97 [Google Scholar]
  85. Platt FM, Hurst CD, Taylor CF, Gregory WM, Hamden P. 85.  et al. 2009. Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin. Cancer Res. 15:6008–17 [Google Scholar]
  86. Askham JM, Platt F, Chambers PA, Snowden H, Taylor CF. 86.  et al. 2010. AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can cooperate with E17K. Oncogene 29:150–55 [Google Scholar]
  87. Navin N, Kendall J, Troge J, Andrews P, Rodgers L. 87.  et al. 2011. Tumour evolution inferred by single-cell sequencing. Nature 472:734190–94 [Google Scholar]
  88. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M. 88.  et al. 1999. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286:5439531–37 [Google Scholar]
  89. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS. 89.  et al. 2000. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:6769503–11 [Google Scholar]
  90. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS. 90.  et al. 2000. Molecular portraits of human breast tumours. Nature 406:6797747–52 [Google Scholar]
  91. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S. 91.  et al. 2001. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. PNAS 98:1910869–74 [Google Scholar]
  92. Visvader JE. 92.  2009. Keeping abreast of the mammary epithelial hierarchy and breast tumorigenesis. Genes Dev. 23:222563–77 [Google Scholar]
  93. 93. Cancer Genome Atlas Network 2012. Comprehensive molecular portraits of human breast tumours. Nature 490:741861–70 [Google Scholar]
  94. Dyrskjot L, Thykjaer T, Kruhoffer M, Jensen JL, Marcussen N. 94.  et al. 2003. Identifying distinct classes of bladder carcinoma using microarrays. Nat. Genet. 33:190–96 [Google Scholar]
  95. Blaveri E, Simko JP, Korkola JE, Brewer JL, Baehner F. 95.  et al. 2005. Bladder cancer outcome and subtype classification by gene expression. Clin. Cancer Res. 11:114044–55 [Google Scholar]
  96. Lindgren D, Sjodahl G, Lauss M, Staaf J, Chebil G. 96.  et al. 2012. Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma. PLoS ONE 7:6e38863 [Google Scholar]
  97. Sjodahl G, Lovgren K, Lauss M, Patschan O, Gudjonsson S. 97.  et al. 2013. Toward a molecular pathologic classification of urothelial carcinoma. Am. J. Pathol. 183:3681–91 [Google Scholar]
  98. Hoadley KA, Yau C, Wolf DM, Cherniack AD, Tamborero D. 98.  et al. 2014. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158:4929–44 [Google Scholar]
  99. Ho PL, Kurtova A, Chan KS. 99.  2012. Normal and neoplastic urothelial stem cells: getting to the root of the problem. Nat. Rev. Urol. 9:10583–94 [Google Scholar]
  100. Varley CL, Stahlschmidt J, Smith B, Stower M, Southgate J. 100.  2004. Activation of peroxisome proliferator-activated receptor-γ reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells. Am. J. Pathol. 164:51789–98 [Google Scholar]
  101. Rebouissou S, Bernard-Pierrot I, de Reynies A, Lepage ML, Krucker C. 101.  et al. 2014. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci. Trans. Med. 6:244244ra291 [Google Scholar]
  102. Varley CL, Stahlschmidt J, Lee WC, Holder J, Diggle C. 102.  et al. 2004. Role of PPAR γ and EGFR signalling in the urothelial terminal differentiation programme. J. Cell Sci. 117:2029–36 [Google Scholar]
  103. Chan KS, Espinosa I, Chao M, Wong D, Ailles L. 103.  et al. 2009. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. PNAS 106:14016–21 [Google Scholar]
  104. Zaret KS, Carroll JS. 104.  2011. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25:2227–41 [Google Scholar]
  105. Jozwik KM, Carroll JS. 105.  2012. Pioneer factors in hormone-dependent cancers. Nat. Rev. Cancer 12:381–85 [Google Scholar]
  106. Kurzrock EA, Lieu DK, Degraffenried LA, Chan CW, Isseroff RR. 106.  2008. Label-retaining cells of the bladder: candiate urothelial stem cells. Am. J. Physiol. Ren. Physiol. 294:F1415–21 [Google Scholar]
  107. He X, Marchionni L, Hansel DE, Yu W, Sood A. 107.  et al. 2009. Differentiation of a highly tumorigenic basal cell compartment in urothelial carcinoma. Stem Cells 27:1487–95 [Google Scholar]
  108. Brandt WD, Matsui W, Rosenberg JE, He X, Ling S. 108.  et al. 2009. Urothelial carcinoma: stem cells on the edge. Cancer Metastasis Rev. 28:291–304 [Google Scholar]
  109. Farsund T. 109.  1976. Cell kinetics of mouse urinary bladder epithelium. II. Changes in proliferation and nuclear DNA content during necrosis regeneration, and hyperplasia caused by a single dose of cyclophosphamide. Virchows Arch. B Cell Pathol. 21:279–98 [Google Scholar]
  110. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. 110.  1999. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708–13 [Google Scholar]
  111. Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. 111.  et al. 2004. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 18:126–31 [Google Scholar]
  112. McKeon F. 112.  2004. p63 and the epithelial stem cell: more than status quo?. Genes Dev. 18:465–69 [Google Scholar]
  113. Cheng W, Jacobs WB, Zhang JJ, Moro A, Park JH. 113.  et al. 2006. ΔNp63 plays an anti-apoptotic role in ventral bladder development. Development 133:4783–92 [Google Scholar]
  114. He S, Nakada D, Morrison SJ. 114.  2009. Mechanisms of stem cell self-renewal. Annu. Rev. Cell Dev. Biol. 25:377–406 [Google Scholar]
  115. Osborn SL, Kurzrock EA. 115.  2015. Production of urothelium from pluripotent stem cells for regenerative applications. Curr. Urol. Rep. 16:466 [Google Scholar]
  116. McCarthy N. 116.  2014. Bladder cancer: finding the origin. Nat. Rev. Cancer 14:386:87 [Google Scholar]
  117. Dancik GM, Owens CR, Iczkowski KA, Theodorescu D. 117.  2014. A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors. Stem Cells 32:974–82 [Google Scholar]
  118. Jinesh GG, Willis DL, Kamat AM. 118.  2014. Bladder cancer stem cells: biological and therapeutic perspectives. Curr. Stem Cell Res. Ther. 9:89–101 [Google Scholar]
  119. Zhu YT, Lei CY, Luo Y, Liu N, He CW. 119.  et al. 2013. A modified method for isolation of bladder cancer stem cells from a MB49 murine cell line. BMC Urol. 13:57 [Google Scholar]
  120. Pignon JC, Grisanzio C, Geng Y, Song J, Shivdasani RA. 120.  et al. 2013. p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia. PNAS 110:8105–10 [Google Scholar]
  121. Miyao N, Tsai YC, Lerner SP, Olumi AF, Spruck CH III. 121.  et al. 1993. Role of chromosome 9 in human bladder cancer. Cancer Res. 53:4066–70 [Google Scholar]
  122. Cairns P, Shaw ME, Knowles MA. 122.  1993. Preliminary mapping of the deleted region of chromosome 9 in bladder cancer. Cancer Res. 53:1230–32 [Google Scholar]
  123. Keen AJ, Knowles MA. 123.  1994. Definition of 2 regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene 9:2083–88 [Google Scholar]
  124. Simoneau AR, Spruck CH III, Gonzalez-Zulueta M, Gonzalgo ML, Chan MF. 124.  et al. 1996. Evidence for two tumor suppressor loci associated with proximal chromosome 9p to q and distal chromosome 9q in bladder cancer and the initial screening for GAS1 and PTC mutations. Cancer Res. 56:5039–43 [Google Scholar]
  125. Cairns JP, Chiang PW, Ramamoorthy S, Kurnit DM, Sidransky D. 125.  1998. A comparison between microsatellite and quantitative PCR analyses to detect frequent p16 copy number changes in primary bladder tumors. Clin. Cancer Res. 4:441–44 [Google Scholar]
  126. Salem C, Liang G, Tsai YC, Coulter J, Knowles MA. 126.  et al. 2000. Progressive increase in de novo methylation of CpG islands in bladder cancer. Cancer Res. 60:2473–76 [Google Scholar]
  127. Williamson MP, Elder PA, Shaw ME, Devlin J, Knowles MA. 127.  1995. p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum. Mol. Genet. 4:1569–77 [Google Scholar]
  128. Hornigold N, Devlin J, Davies AM, Aveyard JS, Habuchi T. 128.  et al. 1999. Mutation of the 9q34 gene TSC1 in sporadic bladder cancer. Oncogene 18:2657–61 [Google Scholar]
  129. Knowles MA, Habuchi T, Kennedy W, Cuthbert-Heavens D. 129.  2003. Mutation spectrum of the 9q34 tuberous sclerosis gene TSC1 in transitional cell carcinoma of the bladder. Cancer Res. 63:7652–56 [Google Scholar]
  130. Chaturvedi V, Li L, Hodges S, Johnston D, Ro JY. 130.  et al. 1997. Superimposed histologic and genetic mapping of chromosome 17 alterations in human urinary bladder neoplasia. Oncogene 14:2059–70 [Google Scholar]
  131. Czerniak B, Li L, Chaturvedi V, Ro JY, Johnston DA. 131.  et al. 2000. Genetic modeling of human urinary bladder carcinogenesis. Genes Chromosomes Cancer 27:392–402 [Google Scholar]
  132. Czerniak B, Chaturvedi V, Li L, Hodges S, Johnston D. 132.  et al. 1999. Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer. Oncogene 18:1185–96 [Google Scholar]
  133. Yoon DS, Li L, Zhang RD, Kram A, Ro JY. 133.  et al. 2001. Genetic mapping and DNA sequence–based analysis of loci on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease. Oncogene 20:365005–14 [Google Scholar]
  134. Kram A, Li L, Zhang RD, Yoon DS, Ro JY. 134.  et al. 2001. Mapping and genome sequence analysis of chromosome 5 regions involved in bladder cancer progression. Lab. Investig. 81:71039–48 [Google Scholar]
  135. Majewski T, Lee S, Jeong J, Yoon DS, Kram A. 135.  et al. 2008. Understanding the development of human bladder cancer by using whole-organ genomic mapping strategy. Lab. Investig. 88:694–721 [Google Scholar]
  136. Kim MS, Jeong J, Majewski T, Kram A, Yoon DS. 136.  et al. 2006. Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia. Lab. Investig. 86:175–90 [Google Scholar]
  137. Lee S, Jeong J, Majewski T, Scherer SE, Kim MS. 137.  et al. 2007. Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. PNAS 104:13732–37 [Google Scholar]
  138. Kalluri R, Weinberg RA. 138.  2009. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 119:61420–28 [Google Scholar]
  139. Peinado H, Olmeda D, Cano A. 139.  2007. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat. Rev. Cancer 7:6415–28 [Google Scholar]
  140. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J. 140.  et al. 2008. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68:197846–54 [Google Scholar]
  141. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A. 141.  et al. 2008. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10:5593–601 [Google Scholar]
  142. Tran MN, Choi W, Wszolek MF, Navai N, Lee IL. 142.  et al. 2013. The p63 isoform ΔNp63α inhibits epithelial-mesenchymal transition in human bladder cancer cells: role of miR-205. J. Biol. Chem. 288:3275–88 [Google Scholar]
  143. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG. 143.  et al. 2013. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154:161–74 [Google Scholar]
  144. Talmadge JE, Wolman SR, Fidler IJ. 144.  1982. Evidence for the clonal origin of spontaneous metastases. Science 217:4557361–63 [Google Scholar]
  145. Yachida S, Jones S, Bozic I, Antal T, Leary R. 145.  et al. 2010. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:73191114–17 [Google Scholar]
  146. Fearon ER, Vogelstein B. 146.  1990. A genetic model for colorectal tumorigenesis. Cell 61:5759–67 [Google Scholar]
  147. Talmadge JE, Fidler IJ. 147.  2010. AACR centennial series: The biology of cancer metastasis: historical perspective. Cancer Res. 70:145649–69 [Google Scholar]
  148. Polyak K, Weinberg RA. 148.  2009. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9:4265–73 [Google Scholar]
  149. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F. 149.  et al. 2011. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145:6926–40 [Google Scholar]
  150. Cheung KJ, Gabrielson E, Werb Z, Ewald AJ. 150.  2013. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155:71639–51 [Google Scholar]
  151. Labelle M, Begum S, Hynes RO. 151.  2011. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20:5576–90 [Google Scholar]
  152. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW. 152.  et al. 2006. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res. 66:2311271–78 [Google Scholar]
  153. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. 153.  2012. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:6725–36 [Google Scholar]
  154. Kim JH, Tuziak T, Hu L, Wang Z, Bondaruk J. 154.  et al. 2005. Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways. Lab. Investig. 85:4532–49 [Google Scholar]
  155. McConkey DJ, Choi W, Marquis L, Martin F, Williams MB. 155.  et al. 2009. Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev. 28:3–4335–44 [Google Scholar]
  156. Slaton JW, Millikan R, Inoue K, Karashima T, Czerniak B. 156.  et al. 2004. Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy. J. Urol. 171:2 Pt 1570–74 [Google Scholar]
  157. Baumgart E, Cohen MS, Silva Neto B, Jacobs MA, Wotkowicz C. 157.  et al. 2007. Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. Clin. Cancer Res. 13:61685–94 [Google Scholar]
  158. Sayan AE, Griffiths TR, Pal R, Browne GJ, Ruddick A. 158.  et al. 2009. SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. PNAS 106:3514884–89 [Google Scholar]
  159. Bruyere F, Namdarian B, Corcoran NM, Pedersen J, Ockrim J. 159.  et al. 2010. Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers. Urol. Oncol. 28:6591–96 [Google Scholar]
  160. Dinney CP, Fishbeck R, Singh RK, Eve B, Pathak S. 160.  et al. 1995. Isolation and characterization of metastatic variants from human transitional cell carcinoma passaged by orthotopic implantation in athymic nude mice. J. Urol. 154:41532–38 [Google Scholar]
  161. Cheng T, Roth B, Choi W, Black PC, Dinney C. 161.  et al. 2013. Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting. PLoS ONE 8:2e57284 [Google Scholar]
  162. Black PC, Dinney CP. 162.  2008. Growth factors and receptors as prognostic markers in urothelial carcinoma. Curr. Urol. Rep. 9:155–61 [Google Scholar]
  163. Izawa JI, Slaton JW, Kedar D, Karashima T, Perrotte P. 163.  et al. 2001. Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder. Oncol. Rep. 8:19–15 [Google Scholar]
  164. Lo HW, Hsu SC, Xia W, Cao X, Shih JY. 164.  et al. 2007. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res. 67:199066–76 [Google Scholar]
  165. Black PC, Brown GA, Inamoto T, Shrader M, Arora A. 165.  et al. 2008. Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clin. Cancer Res. 14:51478–86 [Google Scholar]
  166. Adam L, Zhong M, Choi W, Qi W, Nicoloso M. 166.  et al. 2009. miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin. Cancer Res. 15:165060–72 [Google Scholar]
  167. Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA. 167.  2012. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms. PLoS ONE 7:6e38972 [Google Scholar]
  168. Shah JB, McConkey DJ, Dinney CP. 168.  2011. New strategies in muscle-invasive bladder cancer: on the road to personalized medicine. Clin. Cancer Res. 17:92608–12 [Google Scholar]
  169. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ. 169.  et al. 2003. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl. J. Med. 349:9859–66 [Google Scholar]
  170. Culp SH, Dickstein RJ, Grossman HB, Pretzsch SM, Porten S. 170.  et al. 2014. Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J. Urol. 191:40–47 [Google Scholar]
  171. Svatek RS, Shariat SF, Novara G, Skinner EC, Fradet Y. 171.  et al. 2011. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. Br. J. Urol. Int. 107:898–904 [Google Scholar]
  172. Denkert C, Loibl S, Noske A, Roller M, Muller BM. 172.  et al. 2010. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J. Clin. Oncol. 28:1105–13 [Google Scholar]
  173. Prat A, Ellis MJ, Perou CM. 173.  2012. Practical implications of gene-expression–based assays for breast oncologists. Nat. Rev. Clin. Oncol. 9:148–57 [Google Scholar]
  174. Prowell TM, Pazdur R. 174.  2012. Pathological complete response and accelerated drug approval in early breast cancer. N. Engl. J. Med. 366:262438–41 [Google Scholar]
  175. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N. 175.  et al. 2014. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 4:1140–53 [Google Scholar]
  176. Groenendijk FH, de Jong J, Fransen van de Putte EE, Michaut M, Schlicker A. 176.  et al. 2016. ERBB2 mutations characterize a subgroup of muscle-invasive bladder cancers with excellent response to neoadjuvant chemotherapy. Eur. Urol. 693384–88 [Google Scholar]
  177. Lee JK, Havaleshko DM, Cho H, Weinstein JN, Kaldjian EP. 177.  et al. 2007. A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. PNAS 104:3213086–91 [Google Scholar]
  178. Dinney CP, Hansel D, McConkey D, Shipley W, Hagan M. 178.  et al. 2014. Novel neoadjuvant therapy paradigms for bladder cancer: results from the National Cancer Center Institute Forum. Urol. Oncol. 32:1108–15 [Google Scholar]
  179. McConkey DJ, Choi W, Ochoa A, Siefker-Radtke A, Czerniak B. 179.  et al. 2015. Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer. Hematol. Oncol. Clin. N. Am. 29:377–94 [Google Scholar]
  180. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN. 180.  et al. 2012. Genome sequencing identifies a basis for everolimus sensitivity. Science 338:221 [Google Scholar]
  181. Biton A, Bernard-Pierrot I, Lou Y, Krucker C, Chapeaublanc E. 181.  et al. 2014. Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes. Cell Rep. 9:1235–45 [Google Scholar]
  182. Inoue K, Slaton JW, Karashima T, Yoshikawa C, Shuin T. 182.  et al. 2000. The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Clin. Cancer Res. 6:124866–73 [Google Scholar]
  183. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y. 183.  et al. 2014. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558–62 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error