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EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling
Author(s) -
DeHaan Alyse M.,
Wolters Natalie M.,
Keller Evan T.,
Ignatoski Kathleen M. Woods
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20903
Subject(s) - lncap , cancer research , bone metastasis , prostate cancer , rankl , osteoclast , osteoprotegerin , protein kinase b , growth factor , transforming growth factor , tgf alpha , biology , epidermal growth factor receptor , medicine , endocrinology , cancer , microbiology and biotechnology , signal transduction , activator (genetics) , receptor
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‐α 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‐α 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‐α. Therefore, AKT appeared to be the TGF‐α‐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‐α, which had increased expression of RANKL, an activator of bone remodeling. In concordance, TGF‐α‐treated C4‐2B conditioned medium was able to differentiate an osteoclast precursor line to a greater extent than EGF‐treated C4‐2B or TGF‐α‐treated LNCaP conditioned media. CONCLUSION The switch in EGFR ligand availability as PCa progresses affects cell survival and contributes to bone remodeling. Prostate 69:528–537, 2009. © 2009 Wiley‐Liss, Inc.