Journal
CLINICAL & EXPERIMENTAL METASTASIS
Volume 25, Issue 6, Pages 601-610Publisher
SPRINGER
DOI: 10.1007/s10585-008-9183-1
Keywords
EMT; cell signaling; RANKL; osteoclastogenesis; LIV-1; bone metastasis; prostate; breast; lung; kidney; TGF beta 1; EGF
Categories
Funding
- NCI NIH HHS [P01 CA098912-05, U54 CA119338, R01 CA076620, P01 CA098912-04, P01 CA098912, P01 CA098912-03, P01 CA098912-01A1, CA766201, CA082739, R01 CA082739, R01 CA076620-01A1, P01 CA098912-02, CA098912] Funding Source: Medline
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Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaP(E) from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGF beta 1 plus EGF, IGF-1, beta 2-microglobulin (beta 2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaP(M) were characterized extensively in comparison to the parental ARCaP(E) cells. In addition to expressing mesenchymal biomarkers, ARCaP(M) gained 100% incidence of bone metastasis. ARCaP(M) cells express receptor activator of NF-kappa B ligand (RANKL), which was shown to increase tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in culture, and when metastatic to bone in vivo. We provide evidence that RANKL expression was promoted by increased cell signaling mediated by the activation of Stat3-Snail-LIV-1. RANKL expressed by ARCaP(M) cells is functional both in vitro and in vivo. The lesson we learned from the ARCaP model of EMT is that activation of a specific cell signaling pathway by soluble factors can lead to increased bone turnover, mediated by enhanced RANKL expression by tumor cells, which is implicated in the high incidence of prostate cancer bone colonization. The ARCaP EMT model is highly attractive for developing new therapeutic agents to treat prostate cancer bone metastasis.
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