Mourad Pierre D, Farrell Lindi, Stamps Louis D, Chicoine Michael R, Silbergeld Daniel L
Department of Neurological Surgery, University of Washington, Seattle, WA 98195-6470, USA.
Surg Neurol. 2005 Jun;63(6):511-9; discussion 519. doi: 10.1016/j.surneu.2004.08.062.
Systemic metastasis of glioblastoma multiforme (GBM) in the form of bulk tumor is rare. This could be because of patient death before clinically detectable systemic metastasis, impediments to systemic egress, or the inability of GBM to grow outside the central nervous system (CNS). In the present paper, we tested this last hypothesis.
The delayed brain tumor (DBT) cell was characterized with respect to in vitro and in vivo morphology, growth rate, anchorage-independent growth, glial fibrillary acidic protein expression and cytogenetic analysis, and major histocompatibility complex (MHC) typing. We then assayed implantation-induced intracerebral and systemic GBM growth using 3 rodent models with increasing relative immunologic differences between implanted DBT cells and hosts (Balb/c mice, an isograft, MHC I H2, class type D; C3H mice, an allograft; Wistar rats, a xenograft).
After implantation in the brain, DBT cells generated tumors that were similar to human GBM. Intracerebral DBT implantation as an isograft or allograft produced only intracranial tumors, whereas intracerebral and systemic implantation as a xenograft produced no tumors. Systemic isograft implantation yielded only systemic tumors. Systemic implantation as allografts produced only transient subcutaneous masses.
Delayed brain tumor cells implanted outside the CNS formed tumors unless there was a significant difference between the immunotype of the implanted cells and host. These results support the hypothesis that the rarity of systemic GBM tumors lies in the presence of physical barriers and/or systemic hurdles that prevent their timely growth. These results also demonstrate that GBMs are antigenic, although not immunogenic, with their syngeneic host. Therefore, GBM may be amenable to targeted immunotherapy given successful artificial priming of the immune system.
多形性胶质母细胞瘤（GBM）以大块肿瘤形式发生的全身转移很少见。这可能是因为患者在临床可检测到全身转移之前就已死亡、全身转移存在障碍，或者GBM无法在中枢神经系统（CNS）外生长。在本文中，我们对最后一个假设进行了验证。
对延迟性脑肿瘤（DBT）细胞进行了体外和体内形态学、生长速率、非贴壁依赖性生长、胶质纤维酸性蛋白表达及细胞遗传学分析，以及主要组织相容性复合体（MHC）分型。然后，我们使用3种啮齿动物模型，检测植入诱导的脑内和全身GBM生长情况，植入的DBT细胞与宿主之间的相对免疫差异逐渐增大（Balb/c小鼠，同基因移植，MHC I H2，D类；C3H小鼠，同种异体移植；Wistar大鼠，异种移植）。
将DBT细胞植入脑内后，产生的肿瘤与人GBM相似。作为同基因移植或同种异体移植进行脑内DBT植入仅产生颅内肿瘤，而作为异种移植进行脑内和全身植入则未产生肿瘤。全身同基因移植植入仅产生全身肿瘤。作为同种异体移植进行全身植入仅产生短暂的皮下肿块。
除非植入细胞与宿主的免疫型存在显著差异，否则植入中枢神经系统外的延迟性脑肿瘤细胞会形成肿瘤。这些结果支持以下假设，即全身GBM肿瘤罕见的原因在于存在阻止其及时生长的物理屏障和/或全身障碍。这些结果还表明，GBM具有抗原性，尽管对其同基因宿主无免疫原性。因此，如果成功地对免疫系统进行人工启动，GBM可能适合进行靶向免疫治疗。
