Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Glia. 2010 Jul;58(9):1050-65. doi: 10.1002/glia.20986.
Glial progenitors in the white matter and the subventricular zone are the major population of cycling cells in the postnatal central nervous system, and thought to be candidates for glioma-initiating cells. However, less is known about the dividing cell populations in the brainstem than those in the cerebrum, leading to the lag of basic understanding of brainstem gliomas. We herein demonstrate much fewer cycling glial progenitors exist in the brainstem than in the cerebrum. We also show that infecting brainstem glial progenitors with PDGFB-green fluorescent protein (GFP)-expressing retrovirus induced tumors that closely resembled human malignant gliomas. Of note, brainstem tumors grew more slowly than cerebral tumors induced by the same retrovirus, and >80% tumor cells in the brainstem consisted of GFP-positive, infected progenitors while GFP-positive cells in the cerebral tumors were <20%. These indicate that cerebral tumors progressed rapidly by recruiting resident progenitors via paracrine mechanism whereas brainstem tumors grew more slowly by clonal expansion of the infected population. The cerebral and brainstem glial progenitors similarly showed reversible dedifferentiation upon PDGF stimulation in vitro and did not show the intrinsic difference in terms of the responsiveness to PDGF. We therefore suggest that slower, monoclonal progression pattern of the brainstem tumors is at least partly due to the environmental factors including the cell density of the glial progenitors. Together, these findings are the first implications regarding the cell-of-origin and the gliomagenesis in the brainstem.
胶质祖细胞存在于白质和侧脑室下区，是出生后中枢神经系统中主要的循环细胞群体，被认为是神经胶质瘤起始细胞的候选者。然而，人们对脑干中分裂细胞群体的了解比对大脑中的了解要少，这导致了对脑干神经胶质瘤的基本理解滞后。我们在此证明，脑干中的循环神经胶质祖细胞比大脑中的要少得多。我们还表明，用 PDGFB-绿色荧光蛋白 (GFP)-表达逆转录病毒感染脑干神经胶质祖细胞可诱导与人类恶性神经胶质瘤非常相似的肿瘤。值得注意的是，与相同逆转录病毒诱导的大脑肿瘤相比，脑干肿瘤的生长速度较慢，而脑干肿瘤中 >80%的肿瘤细胞由 GFP 阳性、感染的祖细胞组成，而大脑肿瘤中的 GFP 阳性细胞<20%。这些表明，大脑肿瘤通过旁分泌机制迅速招募内源性祖细胞而迅速进展，而脑干肿瘤通过感染人群的克隆扩增而缓慢生长。体外 PDGF 刺激下，大脑和脑干神经胶质祖细胞同样表现出可逆的去分化，并且对 PDGF 的反应性没有内在差异。因此，我们建议脑干肿瘤的这种较慢、单克隆进展模式至少部分是由于环境因素，包括神经胶质祖细胞的细胞密度所致。总之，这些发现首次提示了脑干肿瘤的起源细胞和神经发生。
