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Orthotopic Mouse Models of Urothelial Cancer

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Urothelial Carcinoma

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1655))

Abstract

Orthotopic mouse models of urothelial cancer are essential for testing novel therapies and molecular manipulations of cell lines in vivo. These models are either established by orthotopic inoculation of human (xenograft models) or murine tumor cells (syngeneic models) in immunocompromised or immune competent mice. Current techniques rely on inoculation by intravesical instillation or direct injection into the bladder wall. Alternative models include the induction of murine bladder tumors by chemical carcinogens (BBN) or genetic engineering (GEM).

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References

  1. Ding J, Xu D, Pan C, Ye M, Kang J, Bai Q, Qi J (2014) Current animal models of bladder cancer: awareness of translatability (Review). Exp Ther Med 8:691–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kubota T (1994) Metastatic models of human cancer xenografted in the nude mouse: the importance of orthotopic transplantation. J Cell Biochem 56:4–8

    Article  CAS  PubMed  Google Scholar 

  3. Chan E, Patel A, Heston W, Larchian W (2009) Mouse orthotopic models for bladder cancer research. BJU Int 104:1286–1291

    Article  PubMed  Google Scholar 

  4. Bhowmick NA, Neilson EG, Moses HL (2004) Stromal fibroblasts in cancer initiation and progression. Nature 432(7015):332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cutz JC, Guan J, Bayani J, Yoshimoto M, Xue H, Sutcliffe M, English J, Flint J, LeRiche J, Yee J, Squire JA, Gout PW, Lam S, Wang YZ (2006) Establishment in severe combined immunodeficiency mice of subrenal capsule xenografts and transplantable tumor lines from a variety of primary human lung cancers: potential models for studying tumor progression-related changes. Clinical Cancer Res 12(13):4043–4054

    Article  CAS  Google Scholar 

  6. Jäger W, Xue H, Hayashi T, Janssen C, Awrey S, Wyatt AW, Anderson S, Moskalev I, Haegert A, Alshalalfa M, Erho N, Davicioni E, Fazli L, Li E, Collins C, Wang Y, Black PC (2015) Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies. Oncotarget 6(25):21522–21532

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pan CX, Zhang H, Tepper CG, Lin TY, Davis RR, Keck J, Ghosh PM, Gill P, Airhart S, Bult C, Gandara DR, Liu E, de Vere White RW (2015) Development and characterization of bladder cancer patient-derived Xenografts for molecularly guided targeted therapy. PLoS One 10(8):e0134346

    Article  PubMed  PubMed Central  Google Scholar 

  8. Summerhayes IC, Franks LM (1979) Effects of donor age on neoplastic transformation of adult mouse bladder epithelium in vitro. J Natl Cancer Inst 62:1017–1023

    CAS  PubMed  Google Scholar 

  9. Arantes-Rodrigues R, Pinto-Leite R, da Costa RG, Colaço A, Lopes C, Oliveira P (2013) Cytogenetic characterization of an N-butyl-N-(4-hydroxybutyl) nitrosamine-induced mouse papillary urothelial carcinoma. Tumour Biol 34:2691–2696

    Article  CAS  PubMed  Google Scholar 

  10. Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR (1999) Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res 59:3512–3517

    CAS  PubMed  Google Scholar 

  11. Hadaschik BA, Black PC, Sea JC, Metwalli AR, Fazli L, Dinney CP, Gleave ME, So AI (2007) A validated mouse model for orthotopic bladder cancer using transurethral tumour inoculation and bioluminescence imaging. BJU Int 100:1377–1384

    Article  PubMed  Google Scholar 

  12. Jäger W, Horiguchi Y, Shah J, Hayashi T, Awrey S, Gust KM, Hadaschik BA, Matsui Y, Anderson S, Bell RH, Ettinger S, So AI, Gleave ME, Lee IL, Dinney CP, Tachibana M, McConkey DJ, Black PC (2013) Hiding in plain view: genetic profiling reveals decades old cross contamination of bladder cancer cell line KU7 with HeLa. J Urol 190(4):1404–1409

    Article  PubMed  PubMed Central  Google Scholar 

  13. Horiguchi Y, Larchian WA, Kaplinsky R, Fair WR, Heston WD (2000) Intravesical liposome-mediated interleukin-2 gene therapy in orthotopic murine bladder cancer model. Gene Ther 7:844–851

    Article  CAS  PubMed  Google Scholar 

  14. Dinney CP, Fishbeck R, Singh RK, Eve B, Pathak S, Brown N, Xie B, Fan D, Bucana CD, Fidler IJ, Killion JJ (1995) Isolation and characterization of metastatic variants from human transitional cell carcinoma passaged by orthotopic implantation in athymic nude mice. J Urol 154:532–1538

    Article  Google Scholar 

  15. Black PC, Shetty A, Brown GA, Esparza-Coss E, Metwalli AR, Agarwal PK, McConkey DJ, Hazle JD, Dinney CP (2010) Validating bladder cancer xenograft bioluminescence with magnetic resonance imaging: the significance of hypoxia and necrosis. BJU Int 106:1799–1804

    Article  PubMed  Google Scholar 

  16. Jager W, Moskalev I, Janssen C, Hayashi T, Awrey S, Gust KM, So AI, Zhang K, Fazli L, Li E, Thuroff JW, Lange D, Black PC (2013) Ultrasound-guided intramural inoculation of orthotopic bladder cancer xenografts: a novel high-precision approach. PLoS One 8(3):e59536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hadaschik BA, Zhang K, So AI, Fazli L, Jia W, Bell JC, Gleave ME, Rennie PS (2008) Oncolytic vesicular stomatitis viruses are potent agents for intravesical treatment of high-risk bladder cancer. Cancer Res 68(12):4506–4510

    Article  CAS  PubMed  Google Scholar 

  18. Adam L, Black PC, Kassouf W, Eve B, McConkey D, Munsell MF, Benedict WF, Dinney CP (2007) Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer. J Urol 177:1900–1906

    Article  CAS  PubMed  Google Scholar 

  19. Cho EJ, Yang J, Mohamedali KA, Lim EK, Kim EJ, Farhangfar CJ, Suh JS, Haam S, Rosenblum MG, Huh YM (2011) Sensitive angiogenesis imaging of orthotopic bladder tumors in mice using a selective magnetic resonance imaging contrast agent containing VEGF121/rGel. Investig Radiol 46:441–449

    Article  Google Scholar 

  20. Ding J, Xu D, Pan C, Ye M, Kang J, Bai Q, Qi J (2014) Current animal models of bladder cancer: awareness of translatability (Review). Exp Ther Med 8:691–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vasconcelos-Nobrega C, Colaco A, Lopes C, Oliveira PA (2012) Review: BBN as an urothelial carcinogen. In Vivo 26:727–739

    CAS  PubMed  Google Scholar 

  22. He Z, Kosinska W, Zhao ZL, Wu XR, Guttenplan JB (2012) Tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine as the basis for urothelial carcinogenesis. Mutat Res 742:92–95

    Article  CAS  PubMed  Google Scholar 

  23. Lubet RA, Huebner K, Fong LY, Altieri DC, Steele VE, Kopelovich L, Kavanaugh C, Juliana MM, Soong SJ, Grubbs CJ (2005) 4- Hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers in mice: characterization of FHIT and survivin expression and chemopreventive effects of indomethacin. Carcinogenesis 26(3):571–578

    Article  CAS  PubMed  Google Scholar 

  24. Shin K, Lim A, Odegaard JI, Honeycutt JD, Kawano S, Hsieh MH, Beachy PA (2014) Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma. Nat Cell Biol 16(5):469–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hicks RM, Wakefield JS (1972) Rapid induction of bladder cancer in rats with N-methyl-N-nitrosourea. Chem Biol Interact 5(2):139–152

    Article  CAS  PubMed  Google Scholar 

  26. Ayala de la Peña F, Kanasaki K, Kanasaki M, Tangirala N, Maeda G, Kalluri R (2011) Loss of p53 and acquisition of angiogenic microRNA profile are insufficient to facilitate progression of bladder urothelial carcinoma in situ to invasive carcinoma. J Biol Chem 286:20778–20787

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wu XR (2009) Biology of urothelial tumorigenesis: insights from genetically engineered mice. Cancer Metastasis Rev 28:281–290

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sharpless NE, Depinho RA (2006) The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov 5:741–754

    Article  CAS  PubMed  Google Scholar 

  29. Politi K, Pao W (2011) How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol 29:2273–2281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR (1999) Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res 59:3512–3517

    CAS  PubMed  Google Scholar 

  31. Ayala de la peña F, Kanasaki K, Kanasaki M, Tangirala N, Maeda G, Kalluri R (2012) Loss of p53 and acquisition of angiogenic microRNA profile are insufficient to facilitate progression of bladder urothelial carcinoma in situ to invasive carcinoma. Biol Chem 286(23):20778–20787

    Article  Google Scholar 

  32. Stone R 2nd, Sabichi AL, Gill J, Lee IL, Adegboyega P, Dai MS, Loganantharaj R, Trutschl M, Cvek U, Clifford JL (2010) Identification of genes correlated with early-stage bladder cancer progression. Cancer Prev Res 3:776–786

    Article  CAS  Google Scholar 

  33. Zhang ZT, Pak J, Huang HY, Shapiro E, Sun TT, Pellicer A, Wu XR (2001) Role of ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20(16):1973–1980

    Article  CAS  PubMed  Google Scholar 

  34. Cheng J, Huang H, Zhang ZT, Shapiro E, Pellicer A, Sun TT, Wu XR (2002) Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res 62:4157–4163

    CAS  PubMed  Google Scholar 

  35. Spiess PE, Czerniak B (2006) Dual-track pathway of bladder carcinogenesis: practical implications. Arch Pathol Lab Med 130(6):844–852

    CAS  PubMed  Google Scholar 

  36. Gao J, Huang HY, Pak J, Cheng J, Zhang ZT, Shapiro E, Pellicer A, Sun TT, Wu XR (2004) p53 deficiency provokes urothelial proliferation and synergizes with activated ha-ras in promoting urothelial tumorigenesis. Oncogene 23:687–696

    Article  CAS  PubMed  Google Scholar 

  37. Mo L, Zheng X, Huang HY, Shapiro E, Lepor H, Cordon-Cardo C, Sun TT, Wu XR (2007) Hyperactivation of ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J Clin Invest 117:314–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang ZT, Pak J, Huang HY, Shapiro E, Sun TT, Pellicer A, Wu XR (2001) Role of ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20:1973–1980

    Article  CAS  PubMed  Google Scholar 

  39. Ahmad I, Patel R, Liu Y, Singh LB, Taketo MM, Wu XR, Leung HY, Sansom OJ (2011) Ras mutation cooperates with β-catenin activation to drive bladder tumourigenesis. Cell Death Dis 2:e124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ahmad I, Morton JP, Singh LB, Radulescu SM, Ridgway RA, Patel S, Woodgett J, Winton DJ, Taketo MM, Wu XR, Leung HY, Sansom OJ (2011) β -catenin activation Synergises with PTEN loss to cause bladder cancer formation. Oncogene 30:178–189

    Article  CAS  PubMed  Google Scholar 

  41. Lin C, Yin Y, Stemler K, Humphrey P, Kibel AS, Mysorekar IU, Ma L (2013) Constitutive β-catenin activation induces male-specific tumorigenesis in the bladder urothelium. Cancer Res 73:5914–5925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, Scorilas A, Klinakis A (2014) A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med 20:1199–1205

    Article  CAS  PubMed  Google Scholar 

  43. Puzio-Kuter AM, Castillo-Martin M, Kinkade CW, Wang X, Shen TH, Matos T, Shen MM, Cordon-Cardo C, Abate-Shen C (2009) Inactivation of p53 and Pten promotes invasive bladder cancer. Genes Dev 23:675–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Santos, M. et al. (2015) NIH Public Access 74:6565–6577.

    Google Scholar 

  45. Ahmad I, Sansom OJ, Leung HY (2012) Exploring molecular genetics of bladder cancer: lessons learned from mouse models. Dis Model Mech 5:323–332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Urology and Paediatric Urology, Johannes Gutenberg-Universität Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Wolfgang Jäger

  2. The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada

    Igor Moskalev, Peter Raven & Akihiro Goriki

  3. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Samir Bidnur & Peter C. Black

Authors
  1. Wolfgang Jäger
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  2. Igor Moskalev
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  3. Peter Raven
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  4. Akihiro Goriki
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  5. Samir Bidnur
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  6. Peter C. Black
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Corresponding author

Correspondence to Wolfgang Jäger .

Editor information

Editors and Affiliations

  1. Department of Urology, Heinrich Heine University, Düsseldorf, Germany

    Wolfgang A Schulz

  2. Department of Urology, Heinrich Heine University, Düsseldorf, Germany

    Michèle J. Hoffmann

  3. Department of Urology, Heinrich Heine University, Düsseldorf, Germany

    Günter Niegisch

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Jäger, W., Moskalev, I., Raven, P., Goriki, A., Bidnur, S., Black, P.C. (2018). Orthotopic Mouse Models of Urothelial Cancer. In: Schulz, W., Hoffmann, M., Niegisch, G. (eds) Urothelial Carcinoma. Methods in Molecular Biology, vol 1655. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7234-0_15

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  • DOI: https://doi.org/10.1007/978-1-4939-7234-0_15

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7233-3

  • Online ISBN: 978-1-4939-7234-0

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