Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma

Kunyoo Shin, Agnes Lim, Justin I. Odegaard, Jared D. Honeycutt, Sally Kawano, Michael H. Hsieh, Philip A. Beachy

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Understanding how malignancies arise within normal tissues requires identification of the cancer cell of origin and knowledge of the cellular and tissue dynamics of tumour progression. Here we examine bladder cancer in a chemical carcinogenesis model that mimics muscle-invasive human bladder cancer. With no prior bias regarding genetic pathways or cell types, we prospectively mark or ablate cells to show that muscle-invasive bladder carcinomas arise exclusively from Sonic hedgehog (Shh)-expressing stem cells in basal urothelium. These carcinomas arise clonally from a single cell whose progeny aggressively colonize a major portion of the urothelium to generate a lesion with histological features identical to human carcinoma in situ. Shh-expressing basal cells within this precursor lesion become tumour-initiating cells, although Shh expression is lost in subsequent carcinomas. We thus find that invasive carcinoma is initiated from basal urothelial stem cells but that tumour cell phenotype can diverge significantly from that of the cancer cell of origin.

Original languageEnglish (US)
Pages (from-to)469-478
Number of pages10
JournalNature Cell Biology
Volume16
Issue number5
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Cell Biology

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    Shin, K., Lim, A., Odegaard, J. I., Honeycutt, J. D., Kawano, S., Hsieh, M. H., & Beachy, P. A. (2014). Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma. Nature Cell Biology, 16(5), 469-478. https://doi.org/10.1038/ncb2956