Knuuttila Matias, Yatkin Emrah, Kallio Jenny, Savolainen Saija, Laajala Teemu D, Aittokallio Tero, Oksala Riikka, Häkkinen Merja, Keski-Rahkonen Pekka, Auriola Seppo, Poutanen Matti, Mäkelä Sari
Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland.
Department of Physiology, University of Turku, Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, Turku, Finland; Functional Foods Forum, University of Turku, Turku, Finland.
Am J Pathol. 2014 Aug;184(8):2163-73. doi: 10.1016/j.ajpath.2014.04.010. Epub 2014 Jun 17.
Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.
雄激素是前列腺癌（PCa）发生和发展的关键因素，雄激素剥夺疗法可抑制PCa生长。然而，在相当一部分接受雄激素剥夺疗法的男性中，PCa会进展为去势抵抗性PCa（CRPC），这使得开发有效的治疗方法具有挑战性。我们使用原位VCaP人PCa异种移植模型来研究雄激素剥夺疗法（去势）后肿瘤的细胞和分子变化。通过每周测量血清前列腺特异性抗原监测肿瘤生长，并将去势后复发肿瘤的小鼠随机分为治疗组。血清前列腺特异性抗原浓度与肿瘤体积显著相关。去势抵抗性肿瘤中肿瘤内雄激素（雄烯二酮、睾酮和5α-二氢睾酮）的浓度与完整宿主中生长的肿瘤相似。因此，去势诱导了参与雄激素合成的酶（CYP17A1、AKR1C3和HSD17B6）的上调，以及全长雄激素受体（AR）和AR剪接变体（AR-V1和AR-V7）的表达。此外，去势抵抗性异种移植中AR靶基因表达得以维持。AR拮抗剂恩杂鲁胺（MDV3100）和ARN-509抑制了去势抵抗性肿瘤的PSA产生，证实了这些肿瘤对雄激素的依赖性。综上所述，这些发现表明我们的VCaP异种移植模型展现了临床CRPC的关键特征，因此为识别可成药靶点以及测试针对CRPC中AR信号传导的治疗策略提供了有价值的工具。
