Song Hong, Shahverdi Karineh, Huso David L, Wang Yuchuan, Fox James J, Hobbs Robert F, Gimi Barjor, Gabrielson Kathleen L, Pomper Martin G, Tsui Benjamin M, Bhujwalla Zaver, Reilly R Todd, Sgouros George
Division of Nuclear Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.
Clin Cancer Res. 2008 Oct 1;14(19):6116-24. doi: 10.1158/1078-0432.CCR-07-4672.
Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies.
The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry.
Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody.
The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.
目前缺乏能够重现患者转移性进展模式的乳腺癌转移动物模型；目前不存在用于评估免疫介导疗法的转移性乳腺癌模型。我们已经开发并表征了一种用于评估免疫介导的转移性乳腺癌疗法的临床前模型。
将NT2.5乳腺肿瘤细胞系注射到免疫耐受的转基因neu-N小鼠和无胸腺裸鼠的左心室中。通过生物发光、小动物磁共振成像、正电子发射断层扫描、单光子发射计算机断层扫描/计算机断层扫描成像以及组织病理学来监测转移进展。通过蛋白质免疫印迹分析和流式细胞术评估正常器官和肿瘤转移灶中的抗原表达。
向左心室注射NT2.5细胞后，在骨骼、肝脏和脾脏中产生了广泛的转移。注射后三到四周，小鼠出现后肢麻痹，偶尔腹部肿大。转移性进展的生物发光成像在裸鼠中成功，但生物发光细胞在有免疫能力的小鼠中被排斥。其他成像方式允许对非生物发光细胞进行成功成像。小动物正电子发射断层扫描成像能够在体内观察到骨骼和肝脏中的疾病。磁共振成像显示肿瘤细胞最初扩散到骨髓。小动物单光子发射计算机断层扫描/计算机断层扫描成像确定了放射性标记抗体靶向的转移性骨病变。
该模型紧密重现了乳腺癌转移扩散的模式。这种免疫耐受的转移模型是现有乳腺癌模型中的新成员，将该模型与体内成像相结合极大地促进了转移性靶向免疫疗法的评估。
