Wharton S B, McNelis U, Bell H S, Whittle I R
Departments of Pathology and Clinical Neurosciences, University of Edinburgh, Edinburgh, Scotland, UK.
Neuropathol Appl Neurobiol. 2000 Dec;26(6):528-35. doi: 10.1046/j.0305-1846.2000.00288.x.
Development of necrosis is a characteristic feature of glioblastoma but its pathogenesis remains poorly understood. The process of poly(ADP-ribosyl)ation in response to DNA damage is mediated by poly(ADP-ribose) polymerase (PARP) and results in NAD+ depletion. The consequent ATP and energy depletion may result in cell necrosis. Therefore PARP activation is a potential candidate for a regulatory role in the pathogenesis of necrosis in glioblastoma. This study investigated whether there might be a relationship between both PARP expression and poly(ADP-ribosyl)ation, and necrosis in glioblastoma. The pattern of expression of PARP and of poly(ADP-ribose) groups in an archival series of glioblastoma was examined using immunohistochemistry. These parameters were also studied in multicellular tumour spheroids, derived from human glioma cell lines in which central necrosis develops with increasing spheroid diameter. Poly(ADP-ribose) groups were expressed in peri-necrotic tumour cells in glioblastoma. In the spheroid model poly(ADP-ribosyl)ation was seen centrally in pre-necrotic and necrotic cells with increasing spheroid diameter. PARP was widely expressed in viable tumour cells in the glioblastoma sections. In the spheroids, PARP expression, which was initially diffuse, became confined to the outer proliferative zone with increasing diameter. The pattern of expression of poly(ADP-ribose) groups in the spheroids and in glioblastoma raises the possibility that poly(ADP-ribosyl)ation may play a role in the development of necrosis in glioma. The high basal PARP expression in both glioblastoma and the spheroids suggests that this enzyme may have additional roles in glioma cell biology.
坏死的发展是胶质母细胞瘤的一个特征性表现，但其发病机制仍知之甚少。响应DNA损伤的聚（ADP - 核糖）基化过程由聚（ADP - 核糖）聚合酶（PARP）介导，并导致NAD + 耗竭。随之而来的ATP和能量耗竭可能导致细胞坏死。因此，PARP激活是胶质母细胞瘤坏死发病机制中具有调节作用的潜在候选因素。本研究调查了PARP表达与聚（ADP - 核糖）基化以及胶质母细胞瘤中的坏死之间是否可能存在关联。使用免疫组织化学检查了一系列存档的胶质母细胞瘤中PARP和聚（ADP - 核糖）基团的表达模式。这些参数也在多细胞肿瘤球体中进行了研究，这些球体源自人胶质瘤细胞系，其中随着球体直径的增加会发生中央坏死。聚（ADP - 核糖）基团在胶质母细胞瘤的坏死周边肿瘤细胞中表达。在球体模型中，随着球体直径增加，在坏死前和坏死细胞的中央可见聚（ADP - 核糖）基化。PARP在胶质母细胞瘤切片中的存活肿瘤细胞中广泛表达。在球体中，最初呈弥漫性的PARP表达随着直径增加而局限于外部增殖区。球体和胶质母细胞瘤中聚（ADP - 核糖）基团的表达模式增加了聚（ADP - 核糖）基化可能在胶质瘤坏死发展中起作用的可能性。胶质母细胞瘤和球体中较高的基础PARP表达表明该酶可能在胶质瘤细胞生物学中具有其他作用。
