Endocrine Abstracts (2016) 42 P3 | DOI: 10.1530/endoabs.42.P3

Diminished response of prostate cancer cells to antiandrogens upon co-culture with cancer-associated fibroblasts as shown in a 3-dimensional prostate cancer epithelial-stromal organoid model

Theresa Eder1,2,3, Anja Weber1, Hannes Neuwirt4, Georg Grünbacher1, Georg Schäfer1, Christian Ploner5, Helmut Klocker1, Natalie Sampson1 & Iris E Eder1

1Department of Urology, Medical University Innsbruck, Innsbruck, Austria; 2Department of Radio Oncology and Radiotherapy, Charité University Hospital, Berlin, Germany; 3German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; 4Department of Internal Medicine IV – Nephrology and Hypertension, Medical University of Innsbruck, Innsbruck, Austria; 5Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Innsbruck, Austria.

The use of more tissue-mimetic 3-dimensional (3D) cell culture models for in vitro drug screening has significantly increased in the past with the expectation to overcome with over-interpretation of drug effects obtained with conventional 2D cultures. In this study, we characterized 3D prostate cancer (PCa) organoids where PCa epithelial cells (LNCaP, DuCaP, LAPC4) were cultured alone or with PCa-associated fibroblasts (CAFs) in 96 well hanging drop plates in order to investigate the influence of the stromal cells on the therapeutic effects of two commonly used antiandrogens (bicalutamide, enzalutamide). All tested PCa cell lines formed so-called organoids and displayed a significant increase in E-cadherin expression, as determined by Western blotting, indicating strong cell-to-cell adhesion upon 3D culture. Interestingly, CAFs seemed to disappear in co-culture organoids by day 8, suggesting that the PCa cells replace the CAFs over time. Organoids displayed androgen responsiveness in 3D culture, however, the effects were less pronounced in PCa/CAF co-culture organoids. Similarly, PCa organoids were less sensitive to the growth-inhibitory effects of the antiandrogens bicalutamide and enzalutamide than 2D cultures, an effect that was further enhanced in co-culture organoids. In LNCaP cells, which are negative for the tumor suppressor gene PTEN, 3D organoids showed increased Akt signaling along with resistance to antiandrogens while AR levels were unchanged. In line with this alteration the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002 significantly inhibited LNCaP organoids, suggesting that targeting Akt could be used to overcome antiandrogen resistance in PTEN negative PCa cells.

Presenting author: Iris E. Eder, Department of Urology, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Email: iris.eder@i-med.ac.at.

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