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-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.