title: Stromal insulin-like growth factor binding protein 3 (IGFBP3) is elevated in the diseased human prostate and promotes ex vivo fibroblast-to-myofibroblast differentiation.
abstract: Dysregulation of the IGF axis is implicated in the development of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), 2 of the most common diseases affecting elderly males. PCa is the second leading cause of male-related cancer death in Western societies. Although distinct pathologies, BPH and PCa are both characterized by extensive stromal remodeling, in particular fibroblast-to-myofibroblast differentiation, thought to be induced by elevated local production of TGFβ1. We previously showed that TGFβ1-mediated fibroblast-to-myofibroblast differentiation of primary human prostatic stromal cells resulted in the dsyregulation of several components of the IGF axis, including the induction of IGF binding protein 3 (IGFBP3). Using isoform-specific lentiviral-mediated knockdown, we demonstrate herein that IGFBP3 is essential for TGFβ1-mediated differentiation. Although recombinant human IGFBP3 alone was not sufficient to induce differentiation, IGFBP3 synergistically potentiated TGFβ1-mediated stromal remodeling predominantly via an IGF-independent mechanism. Consistent with these in vitro findings, IGFBP3 immunohistochemistry revealed elevated levels of IGFBP3 in the hyperplastic fibromuscular stroma of BPH specimens and in the tumor-adjacent stroma of high-grade PCa. Collectively these data indicate that the dysregulation of the stromal IGF axis, in particular elevated IGFBP3, plays a crucial role in fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma and indicate the therapeutic potential of inhibiting stromal remodeling and the resulting dysregulation of the stromal IGF axis as a novel strategy for the treatment of advanced PCa and BPH.
authors.affiliation: Institute for Biomedical Aging Research, Austria. natalie.sampson@i-med.ac.at
authors.forename: Natalie
authors.initials: N
authors.lastname: Sampson
authors.forename: Christoph
authors.initials: C
authors.lastname: Zenzmaier
authors.forename: Martin
authors.initials: M
authors.lastname: Heitz
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Eugen
authors.initials: E
authors.lastname: Plas
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.forename: Peter
authors.initials: P
authors.lastname: Berger
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1