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Development of a three‐dimensional culture model of prostatic epithelial cells and its use for the study of epithelial‐mesenchymal transition and inhibition of PI3K pathway in prostate cancer
Author(s) -
Chu Jian Hong,
Yu Shan,
Hayward Simon W.,
Chan Franky L.
Publication year - 2008
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20897
Subject(s) - matrigel , prostate , epithelial–mesenchymal transition , prostate cancer , du145 , 3d cell culture , cancer research , cell culture , androgen , immortalised cell line , biology , chemistry , lncap , microbiology and biotechnology , endocrinology , medicine , cancer , metastasis , hormone , angiogenesis , genetics
Abstract BACKGROUND Appropriate 3D culture models of human prostatic epithelial cells resembling normal growth pattern and architecture of prostate gland and its malignant development are scarce. METHODS Here, we optimized the 3D culture conditions of the immortalized non‐transformed human prostatic epithelial cell line BPH‐1 in Matrigel and developed a 3D culture model closely mimicking prostatic glandular structure. RESULTS Our results showed that BPH‐1 cells cultured in Matrigel formed acinus‐like spheroids with lumen formation and polarized differentiation. To establish an androgen‐stimulated differentiation in AR‐negative BPH‐1, we generated AR‐transduced BPH‐1 cells, which displayed androgen‐induced secretory differentiation and growth suppression in 3D culture. We also evaluated the spheroid forming capacity of tumorigenic derivative BPH‐1 CAFTD sublines in 3D culture and their responses to PI3K inhibitor LY294002. Results showed that these tumorigenic BPH‐1 CAFTD sublines did not exhibit polarized differentiation in Matrigel culture. Interestingly, polarization could be restored by LY294002 treatment of BPH‐1 CAFTD1 but not of BPH‐1 CAFTD3 subline. Finally, we employed this 3D culture model to examine the significance of an EMT‐regulatory transcription factor Snail in prostate cancer development by its stable transduction into BPH‐1 cells. Results showed that BPH‐1‐Snail cells lost their spheroid forming capacity and exhibited an invasive phenotype. CONCLUSIONS Taken together, we established a 3D culture model of human prostatic epithelial cells with structural and functional relevance to normal prostate gland and prostate cancer development and also demonstrated that this 3D model might be useful to assess the ability of drugs to restore differentiation as a potential surrogate measure of efficacy for prostate cancer therapy. Prostate 69:428–442, 2009. © 2008 Wiley‐Liss, Inc.