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  • Review Article
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Urothelial tumorigenesis: a tale of divergent pathways

Nature Reviews Cancer volume 5, pages 713–725 (2005)Cite this article

Key Points

  • Urothelial tumours arise and evolve through divergent phenotypic pathways. Some tumours progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumours. More aggressive variants arise either from flat, high-grade carcinoma in situ and progress to invasive tumours, or they arise de novo as invasive tumours.

  • These two important phenotypic variants of urothelial tumours exhibit drastically different biological behaviours and prognoses. The low-grade papillary variant is often multifocal and tends to recur, but it infrequently progresses to muscle invasive stages, whereas most of the invasive variants develop into incurable metastases despite radical cystectomy.

  • It is becoming clear that the two urothelial tumour variants harbour distinctive genetic defects: the low-grade non-invasive papillary tumours are characterized by activating mutations in the HRAS gene and fibroblast growth factor receptor 3 gene; and the high-grade invasive tumours are characterized by structural and functional defects in the p53 and retinoblastoma protein (RB) tumour-suppressor pathways.

  • The deletion of both arms of chromosome 9 is prevalent in urothelial carcinomas and occurs during the earliest stages of tumorigenesis. However, these chromosomal aberrations do not seem to distinguish between the two tumour development pathways.

  • Tumour invasion and progression in the bladder seems to be a multifactorial process, promoted by microenvironmental changes that include the upregulation of N-cadherin, the downregulation of E-cadherin, the overexpression of matrix metalloproteinases 2 and 9, an imbalance between angiogenic and anti-angiogenic factors, and increased synthesis of prostaglandin.

  • Urothelial carcinomas are particularly amenable to pathway- and target-based therapies. The low-grade non-invasive papillary tumours could benefit tremendously from receptor tyrosine kinase (RTK)–Ras pathway inhibition by means such as small molecule inhibitors, monoclonal antibodies, farnesyl and geranylgeranyl inhibitors, and RAF and mitogen-activated protein kinase kinase (MEK) inhibitors. The invasive tumours, on the other hand, could benefit from replacement therapies that restore the functions of p53 and RB.

  • The intravesical (within the bladder) route of drug delivery provides a unique advantage because it locally enriches the drug while preventing systemic toxicity in urothelial carcinoma treatment.

  • The identification of specific carcinogens that precipitate each urothelial tumour pathway holds the key to eventually preventing this disease from occurring.

Abstract

Urothelial carcinoma of the bladder is unique among epithelial carcinomas in its divergent pathways of tumorigenesis. Low-grade papillary tumours rarely become muscle-invasive and they frequently harbour gene mutations that constitutively activate the receptor tyrosine kinase–Ras pathway. By contrast, most high-grade invasive tumours progress to life-threatening metastases and have defects in the p53 and the retinoblastoma protein pathways. Correcting pathway-specific defects represents an attractive strategy for the molecular therapy of urothelial carcinomas.

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Figure 1: Important genetic and epigenetic defects that characterize the divergent pathways of urothelial tumorigenesis.
Figure 2: Signalling cascades that are potentially involved in urothelial tumorigenesis during fibroblast growth factor receptor 3 and HRAS gene activation.

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Acknowledgements

The author wishes to acknowledge the useful discussion/comments by members of his laboratory and his collaborators. Research in the author's laboratory is supported by grants from the United States National Institutes of Health and Veterans' Administration. The author regrets that due to space limitation many important studies could not be cited in the article.

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Authors and Affiliations

  1. Departments of Urology and Microbiology, New York University School of Medicine, New York, 10016, New York, USA

    Xue-Ru Wu

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  1. Xue-Ru Wu
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DATABASES

Entrez Gene

CDKN2A

COX2

E-cadherin

EGFR

FGFR3

HRAS

MAD2

MDM2

MMP9

N-cadherin

p53

RB1

TSC1

National Cancer Institute

urothelial carcinoma

FURTHER INFORMATION

American Urological Association homepage

National Cancer Institute progress report on kidney and bladder cancers

Clinical trials on bladder cancer

Glossary

HYPERPLASIA

An increase in the number of cells in a tissue or organ without corresponding gross morphological changes.

ANEUSOMY

Having an abnormal number of chromosomes. Most human epithelial cancers harbour genomes that are characterized by gross aneusomy.

LOSS OF HETEROZYGOSITY

In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of loss of heterozygosity are believed to harbour tumour-suppressor genes.

COMPARATIVE GENOMIC HYBRIDIZATION

A molecular cytogenetic method of screening cells for DNA gains and losses at a chromosomal level. Differentially labelled test and reference DNA are hybridized simultaneously to metaphase chromosomes to generate a map of DNA copy number changes.

ARRAY CGH

Similar to conventional comparative genomic hybridization (CGH), but during hybridization, cloned chromosomal DNA fragments (about 200 kb in size) replace the metaphase chromosomes. This method offers greater sensitivity and resolution than conventional CGH in detecting copy number changes.

HAMARTOMA

A focal benign growth that contains an abnormal proportion of a single cell-type or an abnormal mixture of tissue elements that are normally present at that site. Several hereditary cancer predisposition syndromes also feature hamartomas in several tissues, including tuberous sclerosis and Cowden syndrome.

MATRIGEL

The extracellular matrix secreted by the Engelbreth–Holm–Swarm mouse sarcoma cell-line. It contains laminin, collagen IV, nidogen/entactin and proteoglycans, and so resembles the basement membrane.

ORTHOTOPIC

Of identical anatomical location (orthotopic tumour model: transplantation of tumour tissues into an organ from which the tumour originated).

XENOGRAFT

Tissue (for example, human tumour cells) from one animal species grafted onto another animal species (such as subcutaneously into nude mice).

TRANSDUCTION-ENHANCING AGENT

Chemical agents that can increase the efficiency of gene transfer of viral vectors into the host cells.

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Wu, XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 5, 713–725 (2005). https://doi.org/10.1038/nrc1697

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