title: CXCL12/CXCR4 Axis Activation Mediates Prostate Myofibroblast Phenoconversion through Non-Canonical EGFR/MEK/ERK Signaling.
abstract: Benign prostate hyperplasia (BPH), an enlargement of the prostate common in aging in men, is associated with urinary voiding dysfunction manifest as Lower Urinary Tract Symptoms (LUTS). Although inflammation and abnormal smooth muscle contractions are known to play key roles in the development of LUTS, tissue fibrosis may also be an important and previously unrecognized contributing factor. Tissue fibrosis arises from the unregulated differentiation of fibroblasts or other precursor cell types into myofibroblasts, which is usually accomplished by activation of the TGFβ/TGFβR axis. Previously we reported that the CXC-type chemokines, CXCL5, CXCL8 and CXCL12, which are up-regulated in the aging in the prostate, can drive this differentiation process as well in the absence of TGFβ. Based on this data we sought to elucidate the molecular mechanisms employed by CXCL12, and its receptor CXCR4, during prostate myofibroblast phenoconversion. The results of these studies suggest that CXCL12/CXCR4-mediated signaling events in prostate myofibroblast phenoconversion may proceed through non-canonical pathways that do not depend on TGFβ/TGFβR axis activation or Smad signaling. Here we report that CXCL12/CXCR4 axis activation promotes signaling through the EGFR and downstream MEK/ERK and PI3K/Akt pathways during myofibroblast phenoconversion, but not through TGFβ/TGFβR and downstream Smad signaling, in prostate fibroblasts undergoing myofibroblast phenoconversion. We document that EGFR transactivation is required for CXCL12-mediated signaling and expression of genes associate with myofibroblast phenoconversion (α-SMA, COL1a1). Our study successfully identified TGFβ/TGFβR-independent molecular mechanisms that promote CXCL12/CXCR4-induced myofibroblast phenoconversion. This information may be crucial for the development of novel therapies and potential biomarkers for prostatic fibrosis.
authors.affiliation: Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts.
authors.forename: José A
authors.initials: JA
authors.lastname: Rodríguez-Nieves
authors.affiliation: Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Patalano
authors.affiliation: Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts.
authors.forename: Diego
authors.initials: D
authors.lastname: Almanza
authors.affiliation: Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts.
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Gharaee-Kermani
authors.affiliation: Center for Personalized Cancer Therapy and Department of Biology, University of Massachusetts, Boston, Massachusetts.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Macoska
mesh_terms: D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059411:Lower Urinary Tract Symptoms; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D058628:Myofibroblasts / Q000473:pathology; D011467:Prostate / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I