Document Detail


EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling.
MedLine Citation:
PMID:  19143022     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
CONCLUSION: The switch in EGFR ligand availability as PCa progresses affects cell survival and contributes to bone remodeling.
Authors:
Alyse M DeHaan; Natalie M Wolters; Evan T Keller; Kathleen M Woods Ignatoski
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Prostate     Volume:  69     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-02-25     Completed Date:  2009-03-13     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  528-37     Citation Subset:  IM    
Copyright Information:
(c) 2009 Wiley-Liss, Inc.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / metabolism*,  pathology
Bone Neoplasms / metabolism*,  secondary
Bone Remodeling / drug effects,  physiology*
Cell Line, Tumor
Disease Progression
Epidermal Growth Factor / pharmacology
Humans
Ligands
Male
Mitogen-Activated Protein Kinase Kinases / metabolism
Models, Biological
Neoplasm Staging
Prostatic Neoplasms / metabolism*,  pathology
Proto-Oncogene Proteins c-akt / metabolism
RANK Ligand
Receptor, Epidermal Growth Factor / metabolism*
Signal Transduction / drug effects,  physiology*
Transforming Growth Factor alpha / metabolism,  pharmacology
Grant Support
ID/Acronym/Agency:
P01 CA093900/CA/NCI NIH HHS; R01 CA098513/CA/NCI NIH HHS; R01 CA098513-05/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Ligands; 0/RANK Ligand; 0/TNFSF11 protein, human; 0/Transforming Growth Factor alpha; 62229-50-9/Epidermal Growth Factor; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases
Comments/Corrections

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