Editors' ChoiceCancer

Urothelial Carcinogenesis: A Tale of Two Cells

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Science Translational Medicine  24 Sep 2014:
Vol. 6, Issue 255, pp. 255ec163
DOI: 10.1126/scitranslmed.3010411

Bladder cancer, which includes several histological subtypes, is the sixth most common cancer in the United States. The most common of these subtypes is urothelial carcinoma, which includes carcinoma in situ (CIS), muscle invasive tumors, and papillary lesions and constitutes 90% of the bladder cancer cases in the United States. The remaining 10% include squamous cell carcinoma (SCC) and adenocarcinomas.

Up until now, the identity of the progenitor cells that give rise to these different types of bladder cancer remained controversial. Normal urothelium consists of three subpopulations of cells: the basal K5 layer, an intermediate layer, and a superficial layer, which have different patterns of expression of uroplakin (UPK) and keratin 5 (KRT5). A recent study by Van Batavia and colleagues used an innovative approach to investigate the contribution of each of these cell lineages to the development of different bladder cancer types. The investigators used a site-specific Cre-lox recombination mouse model to label different urothelial cell sub-populations. The intermediate and superficial cells were labeled with the UPK transgene fused to the tamoxifen-inducible Cre recombinase (CreERT2) gene, and the K5-expressing basal layer was labeled by using a similar strategy with KRT5. The researchers bred these animals with different reporter mice, which had either wild-type or heterozygous Trp53 background. Trp53 was selected because of its recognized role in bladder cancer tumorigenesis. The mice were then treated with BBN, a chemical carcinogen known to induce urothelial carcinoma in rodents.

The investigators found that in BBN-treated animals heterozygous for Trp53, K5-basal cells gave rise to CIS and muscle-invasive urothelial carcinoma, whereas the same cell layer gave rise to SCC in mice with wild-type Trp53. The intermediate cell layer and its daughters tended to contribute to papillary carcinomas.

This study sheds light on the lineages of different histopathological types of bladder cancer and shows that the malignant fate of the cells is determined both by the cell of origin and by Trp53 status. This finding opens the door to a better understanding of bladder cancers and ultimately to more rational designs for therapeutic approaches to each type.

J. Van Batavia et al., Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 10.1038/ncb3038 (2014). [Abstract]

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