Martinez D A, Kahwash S, O'Dorisio M S, Lloyd T V, McGhee R B, Qualman S J
Department of Pathology, Ohio State University College of Medicine, Columbus, USA.
Cancer. 1996 Jan 15;77(2):409-19. doi: 10.1002/(SICI)1097-0142(19960115)77:2<409::AID-CNCR26>3.0.CO;2-4.
The overall survival of children with neuroblastoma remains less than 30% due to disease dissemination at the time of diagnosis. An animal model of neuroblastoma, with characteristics similar to those observed clinically in children, would be beneficial to investigations into the diverse biology of this tumor. The purpose of this study was (1) to develop a model of disseminated neuroblastoma in the nude rat by intracardiac injection of neuroblastoma cells derived from cell lines with different N-myc copy numbers; (2) to investigate the effect of age on tumor growth and dissemination; and (3) to assess progression of disease radiologically and correlate with autopsy findings.
Nude rats (n = 38), 5-13 weeks of age, underwent intracardiac injection of the human neuroblastoma cell lines IMR-32 with amplified N-myc oncogene and SKNSH with 1 N-myc copy. The animals were observed for at least six weeks for the development of tumor. Twelve rodents injected with IMR-32 cells underwent imaging studies including magnetic resonance imaging (MRI), skeletal radiographs, and indium-111(IN-111)-diethylenetriamine penta-acetic acid-D-Phe1-octreotide scintigraphy. Autopsies with standardized microscopic examinations were performed on all animals.
Most of the nude rats (95%) developed neuroblastoma following intracardiac injection of neoplastic cells. Disseminated tumor was evident in 66% of animals. Anatomic sites of neuroblastoma growth were similar to those observed clinically in children, including adrenal glands, paraspinal ganglia, bone, bone marrow, and skin, but no tumor was identified in the liver. Disseminated disease occurred in more animals injected with IMR-32 (78% of animals) than with SKNSH cells (34% of animals) (P < 0.05). Tumor spread appeared to be age dependent; only rodents 5-8 weeks old at the time of injection developed disseminated disease when compared with animals 9 weeks of age or older (P < 0.0001). Radioreceptor scintigraphy demonstrated only pericardial tumor; MRI identified pericardial, adrenal gland, and subcutaneous neoplasms; only skeletal radiographs detected neuroblastoma in cortical bone.
(1) Following intracardiac injection of human neuroblastoma cell lines into nude rats, a xenograft model of disseminated disease develops that closely parallels the malignant process in children. (2) Tumor dissemination is associated with the cell line that demonstrates N-myc amplification and with young age of the recipient at the time of injection. (3) Tumor growth and dissemination may be assessed radiologically. (4) This model of human malignancy may offer an opportunity to investigate the pathophysiologic mechanisms underlying tumor development and dissemination in advanced stage neuroblastoma.
由于神经母细胞瘤患儿在诊断时疾病已发生播散，其总体生存率仍低于30%。建立一种具有与临床观察到的儿童神经母细胞瘤相似特征的动物模型，将有助于对该肿瘤多样生物学特性的研究。本研究的目的是：（1）通过心内注射源自不同N - myc拷贝数细胞系的神经母细胞瘤细胞，在裸鼠中建立播散性神经母细胞瘤模型；（2）研究年龄对肿瘤生长和播散的影响；（3）通过影像学评估疾病进展并与尸检结果进行关联。
选取38只5 - 13周龄的裸鼠，经心内注射具有扩增N - myc癌基因的人神经母细胞瘤细胞系IMR - 32和具有1个N - myc拷贝的SKNSH细胞系。观察动物至少6周以观察肿瘤的发生发展。对12只注射IMR - 32细胞的啮齿动物进行影像学检查，包括磁共振成像（MRI）、骨骼X线片和铟 - 111（In - 111） - 二乙烯三胺五乙酸 - D - 苯丙氨酸1 - 奥曲肽闪烁显像。对所有动物进行标准化显微镜检查的尸检。
大多数裸鼠（95%）在心内注射肿瘤细胞后发生神经母细胞瘤。66%的动物出现播散性肿瘤。神经母细胞瘤生长的解剖部位与临床观察到的儿童神经母细胞瘤相似，包括肾上腺、椎旁神经节、骨骼、骨髓和皮肤，但未在肝脏中发现肿瘤。注射IMR - 32细胞的动物中发生播散性疾病的比例（78%）高于注射SKNSH细胞的动物（34%）（P < 0.05）。肿瘤播散似乎与年龄有关；与9周龄及以上的动物相比，仅注射时5 - 8周龄的啮齿动物发生了播散性疾病（P < 0.0001）。放射性受体闪烁显像仅显示心包肿瘤；MRI可识别心包、肾上腺和皮下肿瘤；只有骨骼X线片检测到皮质骨中的神经母细胞瘤。
（1）将人神经母细胞瘤细胞系心内注射到裸鼠后，可建立一种与儿童恶性过程密切相似的播散性疾病异种移植模型。（2）肿瘤播散与显示N - myc扩增的细胞系以及注射时受体的年轻年龄有关。（3）可通过影像学评估肿瘤生长和播散。（4）这种人类恶性肿瘤模型可能为研究晚期神经母细胞瘤肿瘤发生和播散的病理生理机制提供机会。
