Differential expression of HIF-1 in glioblastoma multiforme and anaplastic astrocytoma.
Differential expression of HIF-1 in glioblastoma multiforme and anaplastic astrocytoma.
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DOI：
10.3892/ijo.2012.1555
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发表时间：
2012-10
影响因子：
5.2
通讯作者：
Schmidberger H
中科院分区：
文献类型：
--
作者：
Mayer A;Schneider F;Vaupel P;Sommer C;Schmidberger H
缺氧是介导肿瘤进展和治疗抗性的重要因素，部分通过转录因子缺氧诱导因子（HIF）-1介导的蛋白质组变化。由于多形性胶质母细胞瘤是高度侵袭性肿瘤实体的缩影，而较低级别的星形细胞瘤通常显示出延长的临床病程，因此这些实体之间可能存在缺氧组织区域的程度和相应的HIF-1活性大小的深刻差异。在这项研究中，为了解决这个问题，对11例胶质母细胞瘤和10例间变性星形细胞瘤的连续切片进行了HIF-1α、葡萄糖转运蛋白（GLUT）-1、碳酸酐酶（CA）IX（即，缺氧相关标志物）、Ki 67（增殖）、磷酸化核糖体蛋白S6 [p-rpS 6;哺乳动物雷帕霉素靶蛋白（mTOR）活性]和CD 34（微血管内皮）。对整个肿瘤切片的数字扫描进行配准，以实现后续形态测量操作的几何对应。HIF-1α、GLUT-1和CA IX在所有11例胶质母细胞瘤中均呈阳性表达，且在坏死的邻近组织中优先表达。GLUT-1和CA IX之间有相当大的空间重叠，并且观察到这些蛋白质与平均扩散距离扩大的区域的共定位。相反，10例间变性星形细胞瘤中有8例缺氧相关标志物完全阴性。胶质母细胞瘤还显示出毛细血管间距离的显著更大异质性、更大的扩散限制组织分数、显著更高的mTOR活性和更高增殖率的趋势。在微区域，mTOR和增殖表现出显着的空间重叠与较短的平均扩散距离的地区。总之，导致缺氧相关标志物表达的扩散限制性缺氧是胶质母细胞瘤表型的关键因素，可能是由常氧亚区的生长和增殖失调驱动的。
Hypoxia is an important factor mediating tumor progression and therapeutic resistance, in part through proteome changes mediated by the transcription factor hypoxia-inducible factor (HIF)-1. Since glioblastoma multiforme is the epitome of a highly aggressive tumor entity, while lower-grade astrocytomas often show a prolonged clinical course, a profound difference in the extent of hypoxic tissue areas and corresponding magnitude of HIF-1 activity may exist between these entities. In this study, to address this question, serial sections of 11 glioblastomas and 10 anaplastic astrocytomas were immunostained for HIF-1α, glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX (i.e., hypoxia-related markers), Ki67 (proliferation), phosphorylated ribosomal protein S6 [p-rpS6; mammalian target of rapamycin (mTOR) activity] and CD34 (microvascular endothelium). Digital scans of whole tumor sections were registered to achieve geometric correspondence for subsequent morphometric operations. HIF-1α-, GLUT-1- and CA IX-positive staining was found in all 11 glioblastomas, showing a preferential expression in tissue areas adjacent to necroses. A considerable spatial overlap between GLUT-1 and CA IX, and a colocalization of these proteins with areas of enlarged mean diffusion distances were observed. Conversely, 8 of the 10 anaplastic astrocytomas were completely negative for hypoxia-related markers. The glioblastomas also showed significantly greater heterogeneity of intercapillary distances, larger diffusion-limited tissue fractions, significantly higher mTOR activity and a trend for higher proliferation rates. Microregionally, mTOR and proliferation showed a significant spatial overlap with areas of shorter mean diffusion distances. In conclusion, diffusion-limited hypoxia, leading to the expression of hypoxia-related markers is a pivotal element of the glioblastoma phenotype and may be driven by dysregulated growth and proliferation in normoxic subregions.
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DOI：
10.1016/j.aanat.2010.03.001
发表时间：
2010-05-20
期刊：
Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft
影响因子：
--
作者：
Airley R;Evans A;Mobasheri A;Hewitt SM
通讯作者：
Hewitt SM
影响因子：
37.3
作者：
Dreyfuss JM;Johnson MD;Park PJ
通讯作者：
Park PJ
影响因子：
4.8
作者：
Arsham, AM;Howell, JJ;Simon, MC
通讯作者：
Simon, MC
DOI：
10.1016/0360-3016(88)90313-6
发表时间：
1988-09-01
影响因子：
7
作者：
GROEBE, K;VAUPEL, P
通讯作者：
VAUPEL, P
影响因子：
11.5
作者：
Kwon, SJ;Lee, YJ
通讯作者：
Lee, YJ