Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture.
Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture.
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DOI：
10.3390/ijms17091458
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发表时间：
2016-09-01
影响因子：
5.6
通讯作者：
Eder IE
中科院分区：
文献类型：
--
作者：
Eder T;Weber A;Neuwirt H;Grünbacher G;Ploner C;Klocker H;Sampson N;Eder IE
雄激素受体(AR)靶向治疗仍然是晚期前列腺癌(PCa)的金标准治疗方法；然而，治疗耐药仍然是一个主要的临床问题。为了研究临床使用的抗雄激素药物的治疗效果，我们在这里描述了一种模拟组织的三维(3D)体外模型，在该模型中，PCA细胞单独培养或与PCA相关的成纤维细胞(CAF)共同培养。值得注意的是，随着时间的推移，PCA细胞与CAF的比例显著增加，有利于球体内强烈模拟体内PCA的肿瘤细胞。尽管有CAF的丢失，但对雄激素不敏感甚至被抗雄激素刺激的基质细胞显著影响了PCa细胞对雄激素以及抗雄激素比卡鲁胺和苯扎鲁胺的敏感性。特别是，当与CAF共同培养时，DuCaP细胞对苯扎鲁胺失去了敏感性。在LAPC4/CAF和LNCaP/CAF共培养球体中，CAF的影响不那么明显。此外，3D球体在共培养的球体中E-钙粘附素表达显著增加，波形蛋白大量表达，而AR水平保持不变甚至降低。在LNCaP/CaF球体中，我们进一步发现Akt信号增强，该信号可被磷脂酰肌醇3激酶(PI3K)抑制剂LY294002抑制，从而克服了球体的抗雄激素抵抗。我们的数据表明，CAF对PCa细胞的药物反应有不同程度的影响，进一步表明该椭球模型是一种有价值的体外药物测试工具。
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.
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影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
5.4
作者：
Bu, Huajie;Schweiger, Michal R.;Klocker, Helmut
通讯作者：
Klocker, Helmut
影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
通讯作者：
de Bono, Johann S.
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J
影响因子：
4.8
作者：
Pece, S;Chiariello, M;Gutkind, JS
通讯作者：
Gutkind, JS