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

Nat Cell Biol. 2014 May;16(5):469-78. doi: 10.1038/ncb2956. Epub 2014 Apr 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Butylhydroxybutylnitrosamine
  • Carcinoma / chemically induced
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / pathology*
  • Cell Lineage*
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Disease Models, Animal
  • Genotype
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Time Factors
  • Tumor Burden
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology*
  • Urinary Bladder Neoplasms / chemically induced
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology*
  • Urothelium / metabolism
  • Urothelium / pathology*


  • Hedgehog Proteins
  • Recombinant Fusion Proteins
  • Shh protein, mouse
  • Butylhydroxybutylnitrosamine