Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice:: establishment of a new transplantable in vivo model for malignant glioma
Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice:: establishment of a new transplantable in vivo model for malignant glioma
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DOI：
10.3171/jns.2007.106.4.652
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发表时间：
2007-04-01
影响因子：
4.1
通讯作者：
Laissue, Jean A.
中科院分区：
文献类型：
--
作者：
Smilowitz, Henry M.;Weissenberger, Jakob;Laissue, Jean A.
Object.本研究的目的是通过使用细胞系Tu-9648和Tu-2449来开发和表征一种新的原位、同基因、可移植的小鼠脑肿瘤模型，所述细胞系是先前从胶质细胞酸性蛋白（GFAP）-v-src转基因小鼠中自发产生的肿瘤中分离的。将来自任一克隆的5000至10，000个细胞的1 μ l悬浮液植入同系1360 F1小鼠的纹状体，导致组织学鉴定为恶性神经胶质瘤的肿瘤。先前皮下接种经辐照的自体细胞抑制了显微镜下浸润的恶性胶质瘤的稳健发展。植入肿瘤细胞的未治疗小鼠在12天后被杀死，此时产生的胶质瘤直径为几毫米。免疫组化显示星形胶质细胞标志物GFAP和致癌形式的信号转导和转录激活因子3（Stat 3）。这种形式被称为酪氨酸-705磷酸化的Stat 3，并且在许多恶性实体中发现，包括人类神经胶质瘤。磷酸化的Stat 3是特别突出的，不仅在细胞核中，而且在外周浸润性胶质瘤细胞的质膜，反映持续过度激活的Janus激酶/Stat 3信号转导通路。Tu-2449细胞表现出三种非随机的染色体结构畸变，包括2号染色体长臂缺失和1号和3号染色体之间明显的平衡易位。GFAP-v-src基因定位于18号染色体着丝粒周围区域。高植入率，高级别恶性胶质瘤的起源相似，这些肿瘤的快速，局部浸润性生长，使这种小鼠模型可用于测试人类恶性胶质瘤的新疗法。
Object. The aim of this study was to develop and characterize a new orthotopic, syngeneic, transplantable mouse brain tumor model by using the cell lines Tu-9648 and Tu-2449, which were previously isolated from tumors that arose spontaneously in glial fibrillary acidic protein (GFAP)-v-src transgenic mice.Methods. Striatal implantation of a 1-mu l suspension of 5000 to 10,000 cells from either clone into syngeneic 1360F1 mice resulted in tumors that were histologically identified as malignant gliomas. Prior subcutaneous inoculations with irradiated autologous cells inhibited the otherwise robust development of a microscopically infiltrating malignant glioma. Untreated mice with implanted tumor cells were killed 12 days later, when the resultant gliomas were several millimeters in diameter. Immunohistochemically, the gliomas displayed both the astroglial marker GFAP and the oncogenic form of signal transducer and activator of transcription-3 (Stat3). This form is called tyrosine-705 phosphorylated Stat3, and is found in many malignant entities, including human gliomas. Phosphorylated Stat3 was particularly prominent, not only in the nucleus but also in the plasma membrane of peripherally infiltrating glioma cells, reflecting persistent overactivation of the Janus kinase/Stat3 signal transduction pathway. The Tu-2449 cells exhibited three non-random structural chromosomal aberrations, including a deletion of the long arm of chromosome 2 and an apparently balanced translocation between chromosomes 1 and 3. The GFAP-v-src transgene was mapped to the pericentromeric region of chromosome 18.Conclusions. The high rate of engraftment, the similarity to the high-grade malignant glioma of origin, and the rapid, locally invasive growth of these tumors should make this murine model useful in testing novel therapies for human malignant gliomas.