Tumor-associated macrophages in SHH subgroup of medulloblastomas.
Tumor-associated macrophages in SHH subgroup of medulloblastomas.
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DOI：
10.1158/1078-0432.ccr-14-1144
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发表时间：
2015-03-15
期刊：
影响因子：
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通讯作者：
Asgharzadeh S
中科院分区：
文献类型：
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作者：
Margol AS;Robison NJ;Gnanachandran J;Hung LT;Kennedy RJ;Vali M;Dhall G;Finlay JL;Erdreich-Epstein A;Krieger MD;Drissi R;Fouladi M;Gilles FH;Judkins AR;Sposto R;Asgharzadeh S
儿童髓母细胞瘤可分为至少四个分子亚群，这为降低治疗相关发病率的靶向治疗方法提供了潜力。肿瘤微环境在成神经管细胞瘤中的作用及其对这些分子亚群的贡献尚不清楚。肿瘤微环境已被证明是成人和儿童肿瘤治疗靶点的重要来源。在这项研究中，我们研究了肿瘤相关巨噬细胞（tam）相关基因的表达与成神经管细胞瘤分子亚群相关的假设，并有助于诊断特征。使用人类外显子阵列（n=168）分析基因表达谱，以鉴定成神经管细胞瘤分子亚群和炎症相关基因的表达。在83个髓母细胞瘤样本中分析了45个肿瘤相关和炎症相关基因的表达，以建立预测分子亚群的基因标记。采用免疫组化（IHC）方法对髓母细胞瘤（n=54）中包含四个分子亚组的tam进行评估。建立了包括tam相关基因（CD163, CSF1R）在内的31个基因髓母细胞瘤亚组分类评分，错误分类率为2%。与第3组和第4组相比，Sonic Hedgehog （SHH）亚组肿瘤中炎症相关基因的表达增加，tam的浸润量显著增加（p<0.0001和p<0.0001）。免疫组化数据显示tam的位置与肿瘤细胞增殖之间有很强的相关性。这些数据表明SHH肿瘤在成神经管细胞瘤亚群中具有独特的肿瘤微环境。tam与SHH髓母细胞瘤细胞的相互作用可能促进肿瘤生长，揭示tam是一个潜在的治疗靶点。
Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAMs) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature. Gene expression profiling using Human Exon Array (n=168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n=54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC). A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163, CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (p<0.0001 and p<0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells. These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.