Abstract
Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenocarcinoma / secondary*
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Aminosalicylic Acids / pharmacology
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Aminosalicylic Acids / therapeutic use
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Animals
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Apoptosis / drug effects
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Benzenesulfonates / pharmacology
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Benzenesulfonates / therapeutic use
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Bone Neoplasms / drug therapy
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Bone Neoplasms / secondary*
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation
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Culture Media, Conditioned / metabolism
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Disease Models, Animal
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Docetaxel / pharmacology
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Docetaxel / therapeutic use
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Humans
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Interferons / genetics
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Interferons / metabolism
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Male
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Mesenchymal Stem Cells / pathology*
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Mice
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Mice, Knockout
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Osteoblasts / pathology
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Primary Cell Culture
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / pathology*
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RNA, Small Interfering / metabolism
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Receptors, Interferon / genetics
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Receptors, Interferon / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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STAT1 Transcription Factor / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism
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Tibia / pathology
Substances
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Aminosalicylic Acids
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Benzenesulfonates
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Culture Media, Conditioned
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IFNLR1 protein, human
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IFNLR1 protein, mouse
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Ifnl3 protein, mouse
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NSC 74859
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RNA, Small Interfering
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Receptors, Interferon
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat1 protein, mouse
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Stat3 protein, mouse
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Docetaxel
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Interferons