Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model.
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 TGFbeta1 plus EGF, IGF-1, beta2-microglobulin (beta2-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-kappaB 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.
Zhau
Haiyen E
HE
Molecular Urology & Therapeutics Program, Department of Urology, Emory University School of Medicine, 1365B Clifton Road, Suite 5107, Atlanta, GA 30322, USA. hzhau@emory.edu
Odero-Marah
Valerie
V
Lue
Hui-Wen
HW
Nomura
Takeo
T
Wang
Ruoxiang
R
Chu
Gina
G
Liu
Zhi-Ren
ZR
Zhou
Binhua P
BP
Huang
Wen-Chin
WC
Chung
Leland W K
LW
D001859:Bone Neoplasms / Q000556:secondary; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology*; D015870:Gene Expression; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D009362:Neoplasm Metastasis; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053245:RANK Ligand / Q000096:biosynthesis; D011944:Receptors, Androgen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D053245:RANK Ligand; D011944:Receptors, Androgen