Abstract
Epithelial-mesenchymal transition (EMT) in cancer describes the phenotypic and behavioral changes of cancer cells from indolent to virulent forms with increased migratory, invasive and metastatic potential. EMT can be induced by soluble proteins like transforming growth factor beta1 (TGFbeta1) and transcription factors including Snail and Slug. We utilized the ARCaP(E)/ARCaP(M) prostate cancer progression model and LNCaP clones stably overexpressing Snail to identify novel markers associated with EMT. Compared to ARCaP(E) cells, the highly tumorigenic mesenchymal ARCaP(M) and ARCaP(M1) variant cells displayed a higher incidence of bone metastasis after intracardiac administration in SCID mice. ARCaP(M) and ARCaP(M1) expressed mesenchymal stromal markers of vimentin and N-cadherin in addition to elevated levels of Receptor Activator of NF-kappaB Ligand (RANKL). We observed that both epidermal growth factor (EGF) plus TGFbeta1 treatment and Snail overexpression induced EMT in ARCaP(E) and LNCaP cells, and EMT was associated with increased expression of RANKL protein. Finally, we determined that the RANKL protein was functionally active, promoting osteoclastogenesis in vitro. Our results indicate that RANKL is a novel marker for EMT during prostate cancer progression. RANKL may function as a link between EMT, bone turnover, and prostate cancer skeletal metastasis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Biomarkers, Tumor / metabolism
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Bone Remodeling / drug effects
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Bone Remodeling / genetics
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Cadherins / metabolism
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Carcinoma / genetics
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Carcinoma / immunology
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Carcinoma / metabolism*
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Cell Dedifferentiation / genetics
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Cell Dedifferentiation / immunology
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Epidermal Growth Factor / pharmacology
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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Humans
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Male
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Mesoderm / metabolism*
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Mesoderm / pathology
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Mice
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Mice, SCID
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Neoplasm Metastasis / genetics
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Neoplasm Metastasis / immunology
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Neoplasm Transplantation
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Osteoclasts / immunology
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Osteoclasts / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / immunology
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Prostatic Neoplasms / metabolism*
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RANK Ligand / genetics
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RANK Ligand / immunology
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RANK Ligand / metabolism*
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / metabolism
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Transforming Growth Factor beta1 / pharmacology
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Vimentin / metabolism
Substances
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Biomarkers, Tumor
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Cadherins
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RANK Ligand
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SNAI1 protein, human
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Snai2 protein, mouse
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Snail Family Transcription Factors
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TNFSF11 protein, human
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Transcription Factors
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Transforming Growth Factor beta1
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Vimentin
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Epidermal Growth Factor