前列腺癌人源性异种移植裸鼠模型的建立与治疗
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摘要
目的建立前列腺癌人源性异种移植(patient-derived xenograft,PDX)模型,评价不同治疗方案的抗肿瘤效果。方法将人新鲜的前列腺癌手术标本与基质胶混合后移植入补充有外源性雄激素的裸鼠皮下,连续监测肿瘤生长,评估其保真度并连续传代;将荷瘤鼠分为四组:多西他赛组、去势组、多西他赛联合去势组以及对照组,治疗期间测量肿瘤体积及小鼠体重变化,治疗结束后,检测血清中总前列腺特异性抗原(total prostate specific antigen,tPSA)浓度及组织病理学变化,评估治疗效果。结果成功建立了前列腺癌PDX模型,包括激素敏感型(D17225)和去势抵抗型(C40019)肿瘤,病理学分析发现移植瘤较好的保持了患者原发瘤的主要特征;病理组织学及血清tPSA检测发现多西他赛组及多西他赛联合去势组在D17225模型中显示出良好的治疗效果,且后者抑瘤效果更为明显。结论成功建立了前列腺癌PDX模型并稳定传代,多西他赛单药或联合去势处理对激素敏感型(D17225)前列腺癌PDX模型具有显著治疗效果。
Objective To establish a nude mouse model of prostate cancer patient-derived xenograft(PDX) and using this model to evaluate the anti-tumor effects of different treatment regimens. Methods Fresh prostate cancer surgical specimens were mixed with Matrigel and transplanted into nude mice supplemented with exogenous androgens. Tumor growth was continuously monitored, the fidelity was evaluated, and serial passage was performed. Tumor-bearing mice were divided into four groups: docetaxel, castration, docetaxel combined with castration and control groups. The tumor volume and mouse body weight were measured during treatment. After treatment, serum total prostate specific antigen(tPSA) level and histopathological changes of the tumors were detected. Results The PDX model of prostate cancer was successfully established, including hormone-sensitive(D17225) and castration-resistant(C40019) tumors, which retained the main features of primary tumors. Serum tPSA and other test results showed that docetaxel and docetaxel combined castration inhibited the D17225 tumor growth significantly. Conclusions The PDX model of prostate cancer is successfully established and can be stably passaged. Docetaxel or combined castration therapy show significant therapeutic effects on the hormone-sensitive(D17225) prostate cancer PDX model.
Objective To establish a nude mouse model of prostate cancer patient-derived xenograft(PDX) and using this model to evaluate the anti-tumor effects of different treatment regimens. Methods Fresh prostate cancer surgical specimens were mixed with Matrigel and transplanted into nude mice supplemented with exogenous androgens. Tumor growth was continuously monitored, the fidelity was evaluated, and serial passage was performed. Tumor-bearing mice were divided into four groups: docetaxel, castration, docetaxel combined with castration and control groups. The tumor volume and mouse body weight were measured during treatment. After treatment, serum total prostate specific antigen(tPSA) level and histopathological changes of the tumors were detected. Results The PDX model of prostate cancer was successfully established, including hormone-sensitive(D17225) and castration-resistant(C40019) tumors, which retained the main features of primary tumors. Serum tPSA and other test results showed that docetaxel and docetaxel combined castration inhibited the D17225 tumor growth significantly. Conclusions The PDX model of prostate cancer is successfully established and can be stably passaged. Docetaxel or combined castration therapy show significant therapeutic effects on the hormone-sensitive(D17225) prostate cancer PDX model.
引文
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[2] Lin D,Wyatt A W,Xue H,et al.High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development [J].Cancer Res,2014,74(4):1272-1283.
[3] 田锦成.雄激素对大鼠精囊腺和前列腺组织水通道蛋白表达的影响 [D].四川医科大学,2015.
[4] Inoue T,Terada N,Kobayashi T,et al.Patient-derived xenografts as in vivo models for research in urological malignancies [J].Nat Rev Urol,2017,14(5):267-283.
[5] Wang Y,Revelo MP,Sudilovsky D,et al.Development and characterization of efficient xenograft models for benign and malignant human prostate tissue [J].Prostate,2005,64(2):149-159.
[6] Zhao H,Nolley R,Chen Z,et al.Tissue slice grafts:an in vivo model of human prostate androgen signaling [J].Am J Pathol,2010,177(1):229-239.
[7] Wang Y,Wang JX,Hui X,et al.Subrenal capsule grafting technology in human cancer modeling and translational cancer research [J].Differentiation,2016,91(4-5):15-19.
[8] Nguyen HM,Vessella RL,Morrissey C,et al.LuCaP prostate cancer patient-derived xenografts reflect the molecular heterogeneity of advanced disease and serve as models for evaluating cancer therapeutics [J].Prostate,2017,77(6):654-671.
[9] Mclean DT,Strand DW,Ricke WA.Prostate cancer xenografts and hormone induced prostate carcinogenesis [J].Differentiation,2017,97:23-32.
[10] Cassidy JW,Caldas C,Bruna A.Maintaining tumor heterogeneity in patient-derived tumor xenografts [J].Cancer Res,2015,75(15):2963-2968.
[11] Tung WL,Wang Y,Gout PW,et al.Use of irinotecan for treatment of small cell carcinoma of the prostate [J].Prostate,2011,71(7):675-681.
[12] Risbridger GP,Taylor RA,Clouston D,et al.Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis [J].Eur Urol,2015,67(3):496-503.
[13] Garralda E,Paz K,Lopez-Cases P,et al.Integrated next-generation sequencing and Avatar mouse models for personalized cancer treatment [J].Clin Cancer Res,2014,2476-2484.
[14] Huang Y,Cheng C,Zhang C,et al.Advances in prostate cancer research models:From transgenic mice to tumor xenografting models [J].Asian J Urol,2016,3(2):64-74.
[15] Rea D,Vecchio VD,Palma G,et al.Mouse models in prostate cancer translational research:From xenograft to PDX [J].Biomed Res Int,2016,2016:2016:9750795.