Tsuji Takahiro, Ikeda Hitoshi, Tsuchikawa Takahiro, Kikuchi Kazunori, Baba Tomohisa, Ishizu Akihiro, Yoshiki Takashi
Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan.
Lab Invest. 2005 Jul;85(7):851-61. doi: 10.1038/labinvest.3700292.
Transgenic rats expressing the pX gene of human T lymphocyte virus type-I (HTLV-I) under control of the rat lymphocyte-specific protein tyrosine kinase type-I promoter (lck-pX rats) developed benign epithelial thymomas. When the thymuses of newborn lck-pX rats were transplanted into the subcapsular space of the kidney in other thymectomized lck-pX rats, similar tumors developed in the transplanted thymuses. Following the tumor growth, dissemination in the abdominal cavity and distant metastasis occurred. The tumors were histopathologically similar to the original thymomas, but prominent nuclear atypia and high mitotic activity were present. The Ki-67 index was twice as high as that in the originals. The tumors were transplantable into the subcutis of lck-pX rats, although transplantation of the originals never succeeded. All evidence indicated that malignant transformation of thymoma was induced by the heterotopic transplantation. Expression of the pX transgene in the transformed tumors were significantly reduced. Among host genes, the expression of p16ink4a/ARF, which was significantly upregulated in the originals, was never detected in the transformed tumors. Genomic Southern blots and PCR suggest that homozygous deletion of the p16ink4a/ARF gene may play important roles in malignant transformation in this model. Our model described here is a useful unique model for in vivo malignant transformation.
在大鼠淋巴细胞特异性蛋白酪氨酸激酶I型启动子（lck-pX大鼠）控制下表达人类I型T淋巴细胞病毒（HTLV-I）pX基因的转基因大鼠发生了良性上皮性胸腺瘤。当将新生lck-pX大鼠的胸腺移植到其他胸腺切除的lck-pX大鼠肾脏的被膜下间隙时，移植的胸腺中也出现了类似的肿瘤。随着肿瘤生长，出现了腹腔内播散和远处转移。这些肿瘤在组织病理学上与原发胸腺瘤相似，但存在明显的核异型性和高有丝分裂活性。Ki-67指数是原发肿瘤的两倍。这些肿瘤可移植到lck-pX大鼠的皮下，而原发肿瘤的移植从未成功。所有证据表明，胸腺瘤的恶性转化是由异位移植诱导的。转化肿瘤中pX转基因的表达显著降低。在宿主基因中，原发肿瘤中显著上调的p16ink4a/ARF的表达在转化肿瘤中未被检测到。基因组Southern印迹和PCR表明，p16ink4a/ARF基因的纯合缺失可能在该模型的恶性转化中起重要作用。我们这里描述的模型是一个用于体内恶性转化的有用的独特模型。
