Candolfi Marianela, Curtin James F, Nichols W Stephen, Muhammad Akm G, King Gwendalyn D, Pluhar G Elizabeth, McNiel Elizabeth A, Ohlfest John R, Freese Andrew B, Moore Peter F, Lerner Jonathan, Lowenstein Pedro R, Castro Maria G
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
J Neurooncol. 2007 Nov;85(2):133-48. doi: 10.1007/s11060-007-9400-9. Epub 2007 Sep 15.
Although rodent glioblastoma (GBM) models have been used for over 30 years, the extent to which they recapitulate the characteristics encountered in human GBMs remains controversial. We studied the histopathological features of dog GBM and human xenograft GBM models in immune-deficient mice (U251 and U87 GBM in nude Balb/c), and syngeneic GBMs in immune-competent rodents (GL26 cells in C57BL/6 mice, CNS-1 cells in Lewis rats). All GBMs studied exhibited neovascularization, pleomorphism, vimentin immunoreactivity, and infiltration of T-cells and macrophages. All the tumors showed necrosis and hemorrhages, except the U87 human xenograft, in which the most salient feature was its profuse neovascularization. The tumors differed in the expression of astrocytic intermediate filaments: human and dog GBMs, as well as U251 xenografts expressed glial fibrillary acidic protein (GFAP) and vimentin, while the U87 xenograft and the syngeneic rodent GBMs were GFAP(-) and vimentin(+). Also, only dog GBMs exhibited endothelial proliferation, a key feature that was absent in the murine models. In all spontaneous and implanted GBMs we found histopathological features compatible with tumor invasion into the non-neoplastic brain parenchyma. Our data indicate that murine models of GBM appear to recapitulate several of the human GBM histopathological features and, considering their reproducibility and availability, they constitute a valuable in vivo system for preclinical studies. Importantly, our results indicate that dog GBM emerges as an attractive animal model for testing novel therapies in a spontaneous tumor in the context of a larger brain.
尽管啮齿动物胶质母细胞瘤（GBM）模型已被使用超过30年，但它们在多大程度上重现人类GBM中所遇到的特征仍存在争议。我们研究了免疫缺陷小鼠（裸Balb/c小鼠中的U251和U87 GBM）中的犬GBM和人异种移植GBM模型，以及免疫健全啮齿动物（C57BL/6小鼠中的GL26细胞、Lewis大鼠中的CNS-1细胞）中的同基因GBM。所有研究的GBM均表现出新生血管形成、多形性、波形蛋白免疫反应性以及T细胞和巨噬细胞浸润。除U87人异种移植瘤外，所有肿瘤均显示坏死和出血，U87人异种移植瘤最显著的特征是其丰富的新生血管形成。肿瘤在星形细胞中间丝的表达上存在差异：人和犬GBM以及U251异种移植瘤表达胶质纤维酸性蛋白（GFAP）和波形蛋白，而U87异种移植瘤和同基因啮齿动物GBM为GFAP阴性和波形蛋白阳性。此外，只有犬GBM表现出内皮细胞增殖，这是小鼠模型中不存在的关键特征。在所有自发和植入的GBM中，我们发现了与肿瘤侵袭非肿瘤性脑实质相符的组织病理学特征。我们的数据表明，GBM的小鼠模型似乎重现了人类GBM的一些组织病理学特征，考虑到它们的可重复性和可得性，它们构成了一个有价值的临床前体内研究系统。重要的是，我们的结果表明，犬GBM作为一种有吸引力的动物模型，可用于在更大脑背景下的自发肿瘤中测试新疗法。
