肺腺癌脑转移动物模型的生物发光成像和SPECT/CT的比较
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摘要
目的利用稳定表达荧光素酶的luc+-PC-9人肺腺癌细胞建立肺癌脑转移动物模型,比较生物发光成像和18F-FDG(18F-fluorodeoxyglucose,18F-氟代脱氧葡糖)SPECT/CT在肺癌转移模型中的评估作用。方法将luc+-PC-9细胞悬液经左心室注入BALB/c裸鼠建立肺癌脑转移模型,分别在第4、5周行生物发光成像、~(18)F-FDG SPECT/CT检查观察裸鼠成瘤情况,以H&E染色病理结果为金标准比较两种方法在肺癌转移模型中的作用。结果经左心室注射luc+-PC-9细胞建立肺癌脑转移模型,脑转移成功率85%。肿瘤细胞的个数与发光强度呈正相关,具有较好的线性关系(R2=0.96)。生物发光成像能在颅脑、脊柱和股骨观察到荧光信号,病理结果证实为转移灶。~(18)F-FDG SPECT/CT在脑组织未见明显的代谢浓聚灶,在股骨或脊柱发现代谢浓聚灶,且病理证实均有骨髓转移。结论左心室注射法是建立人肺腺癌脑转移模型的可靠方法。生物发光成像系统在检测脑转移和骨转移具有较高的灵敏度和特异度,能实现实时、动态、无创观察转移瘤的生长情况;~(18)F-FDG SPECT/CT在检测脑转移灶并不具有优势,更适合于检测骨转移灶。
Objective To establish a mouse model of lung adenocarcinoma brain metastasis with human luc+-PC-9 cells stably expressing luciferase and to compare the evaluation values of bioluminescence imaging and18F-FDG(18F-fluorodeoxyglucose) SPECT / CT in these models. Methods Suspension of luc+-PC-9 cells was injected into the left ventricle of BALB / c nude mice to establish a mouse model of brain metastasis from lung cancer. Bioluminescence imaging and18F-FDG SPECT / CT were used to evaluate the metastasis of tumors as compared with HE-staining pathology as a golden standard. Results The success rate of brain metastases was 85% through injecting luc+-PC-9 cells into the left ventricle.The number of tumor cells was positively related to the intensity of light,with a linear correlation( R2= 0. 96). Fluorescence was observed in the brain,spine and femur by bioluminescence imaging,and the metastases were confirmed by H&E pathological examination.18F-FDG SPECT / CT observed abnormal density collective foci in the spine or femur but not in the brain. Conclusions Injection of tumor cell suspension into the mouse left ventricle is a good method to establish a brain metastasis of lung cancer. Bioluminescence has a higher sensitivity and specificity in detecting brain metastasis and bone metastasis,with advantages of real-time,dynamical and non-invasive detection of tumor metastasis growth.18F-FDG SPECT / CT does not have superiority in detection of brain metastases but is suitable for detecting bone metastasis.
Objective To establish a mouse model of lung adenocarcinoma brain metastasis with human luc+-PC-9 cells stably expressing luciferase and to compare the evaluation values of bioluminescence imaging and18F-FDG(18F-fluorodeoxyglucose) SPECT / CT in these models. Methods Suspension of luc+-PC-9 cells was injected into the left ventricle of BALB / c nude mice to establish a mouse model of brain metastasis from lung cancer. Bioluminescence imaging and18F-FDG SPECT / CT were used to evaluate the metastasis of tumors as compared with HE-staining pathology as a golden standard. Results The success rate of brain metastases was 85% through injecting luc+-PC-9 cells into the left ventricle.The number of tumor cells was positively related to the intensity of light,with a linear correlation( R2= 0. 96). Fluorescence was observed in the brain,spine and femur by bioluminescence imaging,and the metastases were confirmed by H&E pathological examination.18F-FDG SPECT / CT observed abnormal density collective foci in the spine or femur but not in the brain. Conclusions Injection of tumor cell suspension into the mouse left ventricle is a good method to establish a brain metastasis of lung cancer. Bioluminescence has a higher sensitivity and specificity in detecting brain metastasis and bone metastasis,with advantages of real-time,dynamical and non-invasive detection of tumor metastasis growth.18F-FDG SPECT / CT does not have superiority in detection of brain metastases but is suitable for detecting bone metastasis.
引文
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[2]Sandler A,Hirsh V,Reck M,et al.An evidence-based review of the incidence of CNS bleeding with anti-VEGF therapy in nonsmall cell lung cancer patients with brain metastases.[J].Lung Cancer,2012,78(1):1-7.
[3]Mujoomdar A,Austin JH,Malhotra R,et al.Clinical predictors of metastatic disease to the brain,from non-small cell lung carcinoma:Primary tumor size,cell type,and lymph node metastases[J].Radiology,2007,242(3):882-888.
[4]Takeshima H,Kuratsu J,Nishi T,et al.Prognostic factors in patients who survived more than 10 years after undergoing surgery for metastatic brain tumors:report of 5 cases and review of the literature[J].Surg Neurol,2002,58(2):118-123.
[5]雷贝,曹杰,沈杰,等.人肺腺癌脑转移动物模型建立及显像的研究[J].中国肺癌杂志,2013,16(8):391-399.
[6]陈愉生,涂洵崴,俞梅娥,等.胸腔原位种植与经左心室注射建立肺癌脑转移动物模型的比较[J].中国实验动物学报,2015,23(5):490-494.
[7]Hastings JW.Chemistries and colors of bioluminescent reactions:a review[J].Gene,1996,173:5–11.
[8]Wilson T,Hastings JW.Bioluminescence[J].Annu Rev Cell Dev Biol,1998,14:197–230.
[9]Li W,Li H,Li J,et al.Self-assembled supramolecular nano vesicles for safe and highly efficient gene delivery to solid tumors[J].Int J Nanomed.2012,7:4661-4677.
[10]Cool SK,Breyne K,Meyer E,et al.Comparison of in vivo optical systems for bioluminescence and fluorescence imaging[J].J Fluoresc,2013,23(5):909-920.
[11]Burrell-Saward H,Rodgers J,Bradley B,et al.A sensitive and reproducible in vivo imaging mouse model for evaluation of drugs against late-stage human African trypanosomiasis[J].J Antimicrob Chemother,2015,70(2):510-517.
[12]Franc BL,Acton PD,Mari C,et al.Small-animal SPECT and SPECT/CT:important tools for preclinical investigation[J].J Nucl Med,2008,49(10):1651-1663.
[13]Devaud C,Rousseau B,Netzer B,et al.Anti-metastatic potential of humanνδ1(+)γδT cellsin an orthotopic mouse xenograft model of colon carcinoma[J].Cancer Immunol Immunother2013,62(7):1199–1210
[14]Wetterwald A,van der Pluijm G,Que I,et al.Optical Imaging of cancer metastasis to bone marrow:A mouse model of minimal residual disease[J].Am J Pathol,2002,160(3)1143-1153.
[15]李奕钊,肖勇,郭晓君.18F-FDG PET/CT在脑转移瘤诊断中的局限性[J].海南医学,2009,20(6):11-13.
[16]Bunyaviroch T,Aggarwai A,Oates ME.Optimied scintigraphic evaluation of infection and inflammation:role of single-phton emission computed tomography/computed tomography fusion imaging[J].Semin Nucl Med,2006,36(4):295-311.