Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas.
Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas.
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DOI：
10.1371/journal.pone.0043339
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Phillips JJ
中科院分区：
文献类型：
--
作者：
Engler JR;Robinson AE;Smirnov I;Hodgson JG;Berger MS;Gupta N;James CD;Molinaro A;Phillips JJ
胶质母细胞瘤(GBM)是一种恶性程度很高的脑肿瘤，预后很差。基底膜的基因表达谱揭示了临床相关的肿瘤亚型，这为更好地了解疾病的发病机制提供了令人兴奋的机会。越来越多的研究结果表明，免疫反应在癌症进展中发挥了作用，但目前尚不清楚免疫反应在不同肿瘤亚型之间的差异及其对预后的影响。利用来自癌症基因组图谱计划和基因表达总库的基因表达数据，我们展示了免疫反应相关基因在成人基底膜(n = 173)和儿童高级别胶质瘤(n = 53)间充质亚型中的丰富表达。在来自加州大学旧金山分校的一个独立的儿童星形细胞瘤队列(n = 24)中，我们将肿瘤分层为亚型，并证实了这些发现。利用新的免疫细胞特异性基因标记，我们证明了在成人和儿童间充质亚型的GBM肿瘤中，小胶质细胞/巨噬细胞相关基因的选择性浓缩。此外，免疫组织化学染色显示，间叶性肿瘤中小胶质细胞/巨噬细胞的数量显著高于非间叶性肿瘤(p = 0.04)。有趣的是，存活时间最短的成人GBM肿瘤小胶质细胞/巨噬细胞相关基因显著丰富，但在儿童GBM中并非如此。CoxBoost多变量模型显示，免疫反应相关基因在成人预后不良基因特征中高度表达，与巨噬细胞募集和激活相关基因的表达与生存关系最强(p<；0.05)，这与预后不良的相关性一致。利用从肿瘤浸润性细胞的定量中获得的小胶质细胞/巨噬细胞高基因信号，我们鉴定了CD4T细胞、粒细胞和小胶质细胞/巨噬细胞特有的基因丰富(n = 573)。这些研究支持免疫反应，特别是小胶质细胞/巨噬细胞反应，在GBM的一个重要亚群的生物学中发挥作用。这一亚型的确定可能对未来的治疗分层很重要。
Glioblastoma (GBM) is a highly malignant brain tumor with a dismal prognosis. Gene expression profiling of GBM has revealed clinically relevant tumor subtypes, and this provides exciting opportunities to better understand disease pathogenesis. Results from an increasing number of studies demonstrate a role for the immune response in cancer progression, yet it is unclear how the immune response differs across tumor subtypes and how it affects outcome. Utilizing gene expression data from The Cancer Genome Atlas Project and the Gene Expression Omnibus database, we demonstrate an enrichment of immune response-related gene expression in the mesenchymal subtype of adult GBM (n = 173) and pediatric high-grade gliomas (n = 53). In an independent cohort of pediatric astrocytomas (n = 24) from UCSF, we stratified tumors into subtypes and confirmed these findings. Using novel immune cell-specific gene signatures we demonstrate selective enrichment of microglia/macrophage-related genes in adult and pediatric GBM tumors of the mesenchymal subtype. Furthermore, immunostaining of adult GBM tumors showed significantly higher cell numbers of microglia/macrophages in mesenchymal versus non-mesenchymal tumors (p = 0.04). Interestingly, adult GBM tumors with the shortest survival had significant enrichment of microglia/macrophage-related genes but this was not true for pediatric GBMs. Consistent with an association with poor outcome, immune response-related genes were highly represented in an adult poor prognosis gene signature, with the expression of genes related to macrophage recruitment and activation being most strongly associated with survival (p<0.05) using CoxBoost multivariate modeling. Using a microglia/macrophage high gene signature derived from quantification of tumor-infiltrating cells in adult GBM, we identified enrichment of genes characteristic of CD4 T cells, granulocytes, and microglia/macrophages (n = 573). These studies support a role for the immune response, particularly the microglia/macrophage response, in the biology of an important subset of GBM. Identification of this subset may be important for future therapeutic stratification.
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影响因子：
3.7
作者：
Abdullaev IF;Rudkouskaya A;Mongin AA;Kuo YH
通讯作者：
Kuo YH
影响因子：
15.9
作者：
Hussain, S. Farzana;Yang, David;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
影响因子：
4.1
作者：
El Andaloussi, Abdeljabar;Lesniak, Maciej S.
通讯作者：
Lesniak, Maciej S.
影响因子：
1.7
作者：
Gerds, Thomas A.;Schumacher, Martin
通讯作者：
Schumacher, Martin
影响因子：
15.9
作者：
El Andaloussi, Abdejabar;Lesniak, Maciej S.
通讯作者：
Lesniak, Maciej S.