Inducible FGFR-1 Activation Leads to Irreversible Prostate Adenocarcinoma and an Epithelial-to-Mesenchymal Transition

Victor D. Acevedo; Rama D. Gangula; Kevin W. Freeman; Rile Li; Youngyou Zhang; Fen Wang; Gustavo E. Ayala; Leif E. Peterson; Michael Ittmann; David M. Spencer

doi:10.1016/j.ccr.2007.11.004

Inducible FGFR-1 Activation Leads to Irreversible Prostate Adenocarcinoma and an Epithelial-to-Mesenchymal Transition

Victor D. Acevedo, Rama D. Gangula, Kevin W. Freeman, Rile Li, Youngyou Zhang, Fen Wang, Gustavo E. Ayala, Leif E. Peterson, Michael Ittmann, David M. Spencer

Houston Methodist

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

247 Scopus citations

Abstract

Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.

Original language	English (US)
Pages (from-to)	559-571
Number of pages	13
Journal	Cancer Cell
Volume	12
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2007.11.004
State	Published - Dec 6 2007

Keywords

CELLBIO
CELLCYCLE

ASJC Scopus subject areas

Cancer Research
Cell Biology
Oncology

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10.1016/j.ccr.2007.11.004

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title = "Inducible FGFR-1 Activation Leads to Irreversible Prostate Adenocarcinoma and an Epithelial-to-Mesenchymal Transition",

abstract = "Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.",

keywords = "CELLBIO, CELLCYCLE",

author = "Acevedo, {Victor D.} and Gangula, {Rama D.} and Freeman, {Kevin W.} and Rile Li and Youngyou Zhang and Fen Wang and Ayala, {Gustavo E.} and Peterson, {Leif E.} and Michael Ittmann and Spencer, {David M.}",

note = "Funding Information: We thank members of the Spencer lab, Jeffrey Rosen, Norman Greenberg, David Rowley and their labs for technical help, invaluable discussion, and reagents. This work was supported by NIH grant nos. U01-CA84296 (V.D.A., R.D.G., M.I., Y.Z., F.W., and D.M.S.), 1F31-GM069044 (V.D.A.), and P50CA058204 (M.I. and G.E.A.). ",

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T1 - Inducible FGFR-1 Activation Leads to Irreversible Prostate Adenocarcinoma and an Epithelial-to-Mesenchymal Transition

AU - Acevedo, Victor D.

AU - Gangula, Rama D.

AU - Freeman, Kevin W.

AU - Li, Rile

AU - Zhang, Youngyou

AU - Wang, Fen

AU - Ayala, Gustavo E.

AU - Peterson, Leif E.

AU - Ittmann, Michael

AU - Spencer, David M.

N1 - Funding Information: We thank members of the Spencer lab, Jeffrey Rosen, Norman Greenberg, David Rowley and their labs for technical help, invaluable discussion, and reagents. This work was supported by NIH grant nos. U01-CA84296 (V.D.A., R.D.G., M.I., Y.Z., F.W., and D.M.S.), 1F31-GM069044 (V.D.A.), and P50CA058204 (M.I. and G.E.A.).

PY - 2007/12/6

Y1 - 2007/12/6

N2 - Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.

AB - Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.

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Inducible FGFR-1 Activation Leads to Irreversible Prostate Adenocarcinoma and an Epithelial-to-Mesenchymal Transition

Abstract

Keywords

ASJC Scopus subject areas

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