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Int. J. Mol. Sci. 2016, 17(9), 1458; doi:10.3390/ijms17091458

Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture

1
Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
2
Translational Radio Oncology Laboratory, Department of Radio oncology and Radiotherapy, Charité University Hospital, 10117 Berlin, Germany
3
German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Site, 10117 Berlin, Germany
4
Department of Internal Medicine IV-Nephrology and Hypertension, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
5
Department of Plastic, Reconstructive & Aesthetic Surgery, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 1 August 2016 / Revised: 26 August 2016 / Accepted: 26 August 2016 / Published: 1 September 2016
(This article belongs to the Collection Advances in Molecular Oncology)
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Abstract

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa cells were cultured alone or with PCa-associated fibroblasts (CAFs). Notably, the ratio of PCa cells to CAFs significantly increased in time in favor of the tumor cells within the spheroids strongly mimicking PCa in vivo. Despite this loss of CAFs, the stromal cells, which were not sensitive to androgen and even stimulated by the anti-androgens, significantly influenced the sensitivity of PCa cells to androgen and to the anti-androgens bicalutamide and enzalutamide. In particular, DuCaP cells lost sensitivity to enzalutamide when co-cultured with CAFs. In LAPC4/CAF and LNCaP/CAF co-culture spheroids the impact of the CAFs was less pronounced. In addition, 3D spheroids exhibited a significant increase in E-cadherin and substantial expression of vimentin in co-culture spheroids, whereas AR levels remained unchanged or even decreased. In LNCaP/CAF spheroids we further found increased Akt signaling that could be inhibited by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002, thereby overcoming the anti-androgen resistance of the spheroids. Our data show that CAFs influence drug response of PCa cells with varying impact and further suggest this spheroid model is a valuable in vitro drug testing tool. View Full-Text
Keywords: prostate cancer; three-dimensional epithelial–stromal spheroids; cancer-associated fibroblasts; anti-androgens; E-cadherin; Akt signaling prostate cancer; three-dimensional epithelial–stromal spheroids; cancer-associated fibroblasts; anti-androgens; E-cadherin; Akt signaling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Eder, T.; Weber, A.; Neuwirt, H.; Grünbacher, G.; Ploner, C.; Klocker, H.; Sampson, N.; Eder, I.E. Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture. Int. J. Mol. Sci. 2016, 17, 1458.

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