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  • Review Article
  • Published:

Modelling bladder cancer in mice: opportunities and challenges

Nature Reviews Cancer volume 15, pages 42–54 (2015)Cite this article

Subjects

Key Points

  • Bladder cancers arise in the urothelium, a specialized epithelium that comprises basal, intermediate and superficial (umbrella) cells. Bladder cancer represents a heterogeneous set of tumours that vary in histopathology, molecular alterations and potentially cells of origin; the vast majority (more than 90%) are urothelial carcinomas, which are the subject of this Review.

  • Basal cells can serve as urothelial progenitors as well as cells of origin of bladder cancer, particularly of more aggressive subtypes; however, other urothelial cell types can also serve as progenitors in normal bladder as well as cells of origin of bladder cancer, potentially of different subtypes.

  • Urothelial carcinomas fall into two major categories: most (approximately 75%) are non-muscle-invasive, which include low-grade superficial (or papillary) and high-grade carcinoma in situ; the remainder (approximately 25%) are muscle-invasive.

  • Most non-muscle-invasive bladder cancers, particularly low-grade tumours, have favourable prognosis; these can be managed clinically with bladder-sparing treatments, which are generally effective but very costly.

  • Muscle-invasive bladder cancers have relatively poor prognosis; those that have not metastasized are often treated by cystectomy (surgical removal of the bladder), which is reasonably effective (5-year survival of approximately 50%) but associated with high morbidity.

  • Metastatic bladder cancer has a very poor prognosis (5-year survival of approximately 15%) and is treated using chemotherapy, which is neither well-tolerated nor highly effective. Unlike many other cancers, neither the prognosis nor treatment of bladder cancer has improved substantially in the past 20 years, and bladder cancer remains a major cause of cancer mortality.

  • The molecular pathways that give rise to low-grade non-muscle-invasive versus high-grade muscle-invasive bladder cancer are distinct but not mutually exclusive. The recent elucidation of genetic and genomic alterations that are prevalent in muscle-invasive bladder cancer provides new avenues for understanding the underlying molecular mechanisms, as well as new targets for therapeutic intervention.

  • Currently available in vivo models of bladder cancer include carcinogen-based and genetically engineered mouse (GEM) models, as well as orthotopic and renal grafting, each of which has advantages and limitations. Bladder cancer is relatively under-represented by GEM models, particularly those that model more aggressive phenotypes.

  • The mouse bladder may be relatively recalcitrant to developing invasive tumours, which has made it challenging to develop GEM models. Other challenges to developing GEM models include inadequate approaches for restricting gene targeting to the urothelium, and particularly to selected cells of origin. Improved GEM models will lead to opportunities for preclinical evaluation of new treatment options for bladder cancer.

Abstract

The prognosis and treatment of bladder cancer have improved little in the past 20 years. Bladder cancer remains a debilitating and often fatal disease, and is among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as to affect its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described, and in particular, few that develop invasive cancer phenotypes. This Review focuses on opportunities for improving the landscape of mouse models of bladder cancer.

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Figure 1: Bladder anatomy.
Figure 2: Clinical stages of bladder cancer.

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Acknowledgements

The authors would like to thank H. Al-Ahmadie, M. Castillo-Martin, G. Iyer, C. Mendelsohn and M. Shen for helpful comments on the manuscript. Work in the authors' laboratories is funded by a Grant-in-Aid for Young Scientists (A) from the Japan Society for the Promotion of Science (to T.K.), a grant from the Urology Care Foundation Research Scholars Program and Dornier MedTech (to T.B.O.), and funding from the National Cancer Institute and the T.J. Martell Foundation for Leukemia, Cancer and AIDS research (to C.A.S.). C.A.S. is is an American Cancer Society Research Professor supported in part by a generous gift from the F.M. Kirby Foundation.

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Authors and Affiliations

  1. Department of Urology, Kyoto University Graduate School of Medicine, 606-8507, Kyoto, Japan

    Takashi Kobayashi

  2. Department of Urology, Columbia University Medical Center,

    Tomasz B. Owczarek, James M. McKiernan & Cory Abate-Shen

  3. Institute of Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, 10032, New York, USA

    Tomasz B. Owczarek & Cory Abate-Shen

  4. Department of Systems Biology, Columbia University Medical Center, New York, 10032, New York, USA

    Cory Abate-Shen

  5. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, 10032, New York, USA

    Cory Abate-Shen

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  1. Takashi Kobayashi
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PowerPoint slides

Glossary

Non-muscle-invasive bladder cancer

Urothelial carcinomas that do not invade the bladder muscle.

Muscle-invasive bladder cancer

Urothelial carcinomas that invade the muscle layer.

Urothelium

The epithelium that lines the bladder; it comprises basal, intermediate and umbrella cell types.

Lamina propria

The layer of connective tissue that underlies the urothelium.

Detrusor muscle

The layer of smooth muscle that lines the bladder and controls the elimination of urine.

Uroplakin proteins

Transmembrane proteins that comprise the asymmetric unit membrane on the lumen-facing side of the umbrella cells, providing a barrier against the entry of urine.

Papillary tumours

Extrusions of the urothelium into the bladder lumen without invasion of the muscle layer.

Carcinoma in situ

(CIS). A flattened malignant transformation of the urothelium that is presumed to be a precursor of muscle-invasive bladder cancer.

Transurethral resection

(TUR). Endoscopic surgical removal of bladder tumours or lesions

Intravesical therapy

Delivery of interventional or therapeutic agents directly to the bladder lumen.

Bacillus Calmette–Guerin

(BCG). A form of immunotherapy; a front-line intravesical treatment for high-risk non-muscle-invasive bladder cancer.

Cystectomy

Surgical removal of the bladder; the front-line treatment for muscle-invasive bladder cancer.

Autochthonous

Arising within the individual, usually refers to tumours arising de novo in genetically engineered mouse models.

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Kobayashi, T., Owczarek, T., McKiernan, J. et al. Modelling bladder cancer in mice: opportunities and challenges. Nat Rev Cancer 15, 42–54 (2015). https://doi.org/10.1038/nrc3858

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