Kawasoe Takuma, Takeshima Hideo, Yamashita Shinji, Mizuguchi Sohei, Fukushima Tsuyoshi, Yokogami Kiyotaka, Yamasaki Kouji
Department of Neurosurgery, Division of Clinical Neuroscience, and.
J Neurosurg. 2015 Feb;122(2):317-23. doi: 10.3171/2014.10.JNS132159. Epub 2014 Nov 21.
Glioblastoma multiforme (GBM), one of the most aggressive tumors in humans, is highly angiogenic. However, treatment with the angiogenesis inhibitor bevacizumab has not significantly prolonged overall patient survival times. GBM resistance to angiogenesis inhibitors is attributed to multiple interacting mechanisms. Although mesenchymal transition via glioma stem-like cells has attracted attention, it is considered a poor biomarker. There is no simple method for differentiating tumor-derived and reactive vascular cells from normal cells. The authors attempted to detect the mesenchymal transition of tumor cells by means of p53 and isocitrate dehydrogenase 1 (IDH1) immunohistochemistry.
Using antibody against p53 and IDH1 R132H, the authors immunohistochemically analyzed GBM tissue from patients who had undergone surgery at the University of Miyazaki Hospital during August 2005-December 2011. They focused on microvascular proliferation with a p53-positive ratio exceeding 50%. They compared TP53 mutations in original tumor tissues and in p53-positive and p53-negative microvascular proliferation cells collected by laser microdissection.
Among 61 enrolled GBM patients, the first screening step (immunostaining) identified 46 GBMs as p53 positive, 3 of which manifested areas of prominent p53-positive microvascular proliferation (>50%). Histologically, areas of p53-positive microvascular proliferation tended to be clustered, and they coexisted with areas of p53-negative microvascular proliferation. Both types of microvascular proliferation cells were clearly separated from original tumor cells by glial fibrillary acidic protein, epidermal growth factor receptor, and low-/high-molecular-weight cytokeratin. DNA sequencing analysis disclosed that p53-positive microvascular proliferation cells exhibited TP53 mutations identical to those observed in the original tumor; p53-negative microvascular proliferation cells contained a normal allele. Although immunostaining indicated that 3 (2 primary and 1 secondary) of the 61 GBMs were positive for IDH1, no tumors contained microvascular proliferation cells positive for IDH1 R132H.
Some microvascular proliferation clusters in GBM result from mesenchymal transition. The identification of useful markers might reveal this phenomenon as an infrequent event in GBMs.
多形性胶质母细胞瘤（GBM）是人类最具侵袭性的肿瘤之一，具有高度血管生成性。然而，使用血管生成抑制剂贝伐单抗治疗并未显著延长患者的总体生存时间。GBM对血管生成抑制剂的耐药性归因于多种相互作用的机制。尽管通过胶质瘤干细胞样细胞进行的间充质转化已引起关注，但它被认为是一种不良的生物标志物。目前尚无简单方法区分肿瘤来源的血管细胞和反应性血管细胞与正常细胞。作者试图通过p53和异柠檬酸脱氢酶1（IDH1）免疫组化检测肿瘤细胞的间充质转化。
作者使用抗p53和IDH1 R132H抗体，对2005年8月至2011年12月在宫崎大学医院接受手术的患者的GBM组织进行免疫组化分析。他们关注p53阳性率超过50%的微血管增殖情况。他们比较了原发肿瘤组织以及通过激光显微切割收集的p53阳性和p53阴性微血管增殖细胞中的TP53突变情况。
在61例纳入研究的GBM患者中，第一步筛查（免疫染色）确定46例GBM为p53阳性，其中3例表现出显著的p53阳性微血管增殖区域（>50%）。组织学上，p53阳性微血管增殖区域倾向于聚集，且与p53阴性微血管增殖区域共存。两种类型的微血管增殖细胞通过胶质纤维酸性蛋白、表皮生长因子受体以及低/高分子量细胞角蛋白与原发肿瘤细胞明显区分开来。DNA测序分析显示，p53阳性微血管增殖细胞表现出与原发肿瘤中观察到的相同的TP53突变；p53阴性微血管增殖细胞含有一个正常等位基因。尽管免疫染色表明61例GBM中有3例（2例原发和1例继发）IDH1呈阳性，但没有肿瘤含有IDH1 R132H阳性的微血管增殖细胞。
GBM中的一些微血管增殖簇是由间充质转化导致的。有用标志物的鉴定可能会揭示这种现象在GBM中是一种罕见事件。
