Abstract
Prevailing theories suggest that luminal cells are the origin of prostate cancer because it is histologically defined by basal cell loss and malignant luminal cell expansion. We introduced a series of genetic alterations into prospectively identified populations of murine basal/stem and luminal cells in an in vivo prostate regeneration assay. Stromal induction of FGF signaling, increased expression of the ETS family transcription factor ERG1, and constitutive activation of PI3K signaling were evaluated. Combination of activated PI3K signaling and heightened androgen receptor signaling, which is associated with disease progression to androgen independence, was also performed. Even though luminal cells fail to respond, basal/stem cells demonstrate efficient capacity for cancer initiation and can produce luminal-like disease characteristic of human prostate cancer in multiple models. This finding provides evidence in support of basal epithelial stem cells as one target cell for prostate cancer initiation and demonstrates the propensity of primitive cells for tumorigenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Disease Models, Animal
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology*
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Female
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Fibroblast Growth Factor 10 / pharmacology
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Flow Cytometry
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Humans
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, SCID
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Mice, Transgenic
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology*
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Prostatic Neoplasms / physiopathology
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Proto-Oncogene Protein c-fli-1 / genetics
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Proto-Oncogene Protein c-fli-1 / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Regeneration
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Stem Cells / drug effects
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Stem Cells / metabolism
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Stem Cells / pathology*
Substances
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Fibroblast Growth Factor 10
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Fli1 protein, mouse
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Proto-Oncogene Protein c-fli-1
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Receptors, Androgen
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Phosphatidylinositol 3-Kinases
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt