title: EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling.
abstract: BACKGROUND
  Bone metastasis occurs frequently in advanced prostate cancer (PCa) patients; however, it is not known why this happens. The epidermal growth factor receptor (EGFR) ligand EGF is available to early stage PCa; whereas, TGF-alpha is available when PCa metastasizes. Since the microenvironment of metastases has been shown to play a role in the survival of the tumor, we examined whether the ligands had effects on cell survival and proliferation in early and late PCa.
  
  
  METHODS
  We used LNCaP cells as a model of early stage, non-metastatic PCa and the isogenic C4-2B cells as a model of late stage, metastatic PCa.
  
  
  RESULTS
  We found that the proliferation factor MAPK and the survival factor AKT were differentially activated in the presence of different ligands. TGF-alpha induced growth of C4-2B cells and not of the parental LNCaP cells; however, LNCaP cells expressing a constitutively active AKT did proliferate with TGF-alpha. Therefore, AKT appeared to be the TGF-alpha-responsive factor for survival of the late stage PCa cells. LNCaP cells exposed to EGF produced more osteoprotegerin (OPG), an inhibitor of bone remodeling, than C4-2B cells with TGF-alpha, which had increased expression of RANKL, an activator of bone remodeling. In concordance, TGF-alpha-treated C4-2B conditioned medium was able to differentiate an osteoclast precursor line to a greater extent than EGF-treated C4-2B or TGF-alpha-treated LNCaP conditioned media.
  
  
  CONCLUSIONS
  The switch in EGFR ligand availability as PCa progresses affects cell survival and contributes to bone remodeling.
authors.affiliation: Department of Urology, University of Michigan Health System, Ann Arbor, Michigan 48109-0654, USA.
authors.forename: Alyse M
authors.initials: AM
authors.lastname: DeHaan
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Wolters
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Kathleen M Woods
authors.initials: KM
authors.lastname: Ignatoski
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008024:Ligands; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases