Epithelial to mesenchymal transition (EMT) in human prostate cancer: Lessons learned from ARCaP model

Haiyen E. Zhau; Valerie Odero-Marah; Hui Wen Lue; Takeo Nomura; Ruoxiang Wang; Gina Chu; Zhi Ren Liu; Binhua P. Zhou; Wen Chin Huang; Leland W.K. Chung

doi:10.1007/s10585-008-9183-1

Epithelial to mesenchymal transition (EMT) in human prostate cancer: Lessons learned from ARCaP model

Haiyen E. Zhau, Valerie Odero-Marah, Hui Wen Lue, Takeo Nomura, Ruoxiang Wang, Gina Chu, Zhi Ren Liu, Binhua P. Zhou, Wen Chin Huang, Leland W.K. Chung

Research output: Contribution to journal › Article › peer-review

136 Scopus citations

Abstract

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 TGFβ1 plus EGF, IGF-1, β2-microglobulin (β2-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-κB 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.

Original language	English
Pages (from-to)	601-610
Number of pages	10
Journal	Clinical and Experimental Metastasis
Volume	25
Issue number	6
DOIs	https://doi.org/10.1007/s10585-008-9183-1
State	Published - Oct 2008

Bibliographical note

Funding Information:
Acknowledgements We thank Gary Mawyer for editing. The helpful discussion and support from Guodong Zhu, Weiping Qian, Daqing Wu and Clayton Yates are greatly appreciated. The authors are particularly indebted to the helpful suggestions made by the editors, Drs. Rik Thompson and Elizabeth Williams, during the revision of this manuscript. This study was supported in part by CA082739 (HYEZ), U54 CA119338, CA098912 and CA766201 (LWKC). We are grateful to the generous gift from Frances and Clarence Wilkins in support of this study.

Keywords

Bone metastasis
Breast
Cell signaling
EGF
EMT
Kidney
LIV-1
Lung
Osteoclastogenesis
Prostate
RANKL
TGFβ1

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10585-008-9183-1

Cite this

@article{5919a19ae9d04a949b72e21f3a027d1d,

title = "Epithelial to mesenchymal transition (EMT) in human prostate cancer: Lessons learned from ARCaP model",

abstract = "Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaPE from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFβ1 plus EGF, IGF-1, β2-microglobulin (β2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaPM were characterized extensively in comparison to the parental ARCaPE cells. In addition to expressing mesenchymal biomarkers, ARCaPM gained 100% incidence of bone metastasis. ARCaPM cells express receptor activator of NF-κB 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 ARCaPM 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.",

keywords = "Bone metastasis, Breast, Cell signaling, EGF, EMT, Kidney, LIV-1, Lung, Osteoclastogenesis, Prostate, RANKL, TGFβ1",

author = "Zhau, {Haiyen E.} and Valerie Odero-Marah and Lue, {Hui Wen} and Takeo Nomura and Ruoxiang Wang and Gina Chu and Liu, {Zhi Ren} and Zhou, {Binhua P.} and Huang, {Wen Chin} and Chung, {Leland W.K.}",

note = "Funding Information: Acknowledgements We thank Gary Mawyer for editing. The helpful discussion and support from Guodong Zhu, Weiping Qian, Daqing Wu and Clayton Yates are greatly appreciated. The authors are particularly indebted to the helpful suggestions made by the editors, Drs. Rik Thompson and Elizabeth Williams, during the revision of this manuscript. This study was supported in part by CA082739 (HYEZ), U54 CA119338, CA098912 and CA766201 (LWKC). We are grateful to the generous gift from Frances and Clarence Wilkins in support of this study.",

year = "2008",

month = oct,

doi = "10.1007/s10585-008-9183-1",

language = "English",

volume = "25",

pages = "601--610",

number = "6",

}

TY - JOUR

T1 - Epithelial to mesenchymal transition (EMT) in human prostate cancer

T2 - Lessons learned from ARCaP model

AU - Zhau, Haiyen E.

AU - Odero-Marah, Valerie

AU - Lue, Hui Wen

AU - Nomura, Takeo

AU - Wang, Ruoxiang

AU - Chu, Gina

AU - Liu, Zhi Ren

AU - Zhou, Binhua P.

AU - Huang, Wen Chin

AU - Chung, Leland W.K.

N1 - Funding Information: Acknowledgements We thank Gary Mawyer for editing. The helpful discussion and support from Guodong Zhu, Weiping Qian, Daqing Wu and Clayton Yates are greatly appreciated. The authors are particularly indebted to the helpful suggestions made by the editors, Drs. Rik Thompson and Elizabeth Williams, during the revision of this manuscript. This study was supported in part by CA082739 (HYEZ), U54 CA119338, CA098912 and CA766201 (LWKC). We are grateful to the generous gift from Frances and Clarence Wilkins in support of this study.

PY - 2008/10

Y1 - 2008/10

N2 - Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaPE from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFβ1 plus EGF, IGF-1, β2-microglobulin (β2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaPM were characterized extensively in comparison to the parental ARCaPE cells. In addition to expressing mesenchymal biomarkers, ARCaPM gained 100% incidence of bone metastasis. ARCaPM cells express receptor activator of NF-κB 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 ARCaPM 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.

AB - Androgen refractory cancer of the prostate (ARCaP) cells contain androgen receptor (AR) and synthesize and secrete prostate specific antigen (PSA). We isolated epithelia-like ARCaPE from parental ARCaP cells and induced them to undergo epithelial-mesenchymal transition (EMT) by exposing these cells to soluble factors including TGFβ1 plus EGF, IGF-1, β2-microglobulin (β2-m), or a bone microenvironment. The molecular and behavioral characteristics of the resultant ARCaPM were characterized extensively in comparison to the parental ARCaPE cells. In addition to expressing mesenchymal biomarkers, ARCaPM gained 100% incidence of bone metastasis. ARCaPM cells express receptor activator of NF-κB 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 ARCaPM 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.

KW - Bone metastasis

KW - Breast

KW - Cell signaling

KW - EGF

KW - EMT

KW - Kidney

KW - LIV-1

KW - Lung

KW - Osteoclastogenesis

KW - Prostate

KW - RANKL

KW - TGFβ1

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U2 - 10.1007/s10585-008-9183-1

DO - 10.1007/s10585-008-9183-1

M3 - Article

C2 - 18535913

AN - SCOPUS:47549095025

SN - 0262-0898

VL - 25

SP - 601

EP - 610

JO - Clinical and Experimental Metastasis

JF - Clinical and Experimental Metastasis

IS - 6

ER -

Epithelial to mesenchymal transition (EMT) in human prostate cancer: Lessons learned from ARCaP model

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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