title: Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma.
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.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kunyoo
authors.initials: K
authors.lastname: Shin
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Lim
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Justin I
authors.initials: JI
authors.lastname: Odegaard
authors.affiliation: Stanford Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Jared D
authors.initials: JD
authors.lastname: Honeycutt
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Kawano
authors.affiliation: Department of Urology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA [4] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000818:Animals; D002085:Butylhydroxybutylnitrosamine; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005838:Genotype; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology*
chemical_list: D053823:Hedgehog Proteins; D011993:Recombinant Fusion Proteins; C465570:Shh protein, mouse; D002085:Butylhydroxybutylnitrosamine
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