Donson Andrew M, Apps John, Griesinger Andrea M, Amani Vladimir, Witt Davis A, Anderson Richard C E, Niazi Toba N, Grant Gerald, Souweidane Mark, Johnston James M, Jackson Eric M, Kleinschmidt-DeMasters Bette K, Handler Michael H, Tan Aik-Choon, Gore Lia, Virasami Alex, Gonzalez-Meljem Jose Mario, Jacques Thomas S, Martinez-Barbera Juan Pedro, Foreman Nicholas K, Hankinson Todd C
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Developmental Biology and Cancer Programme, Great Ormond Street UCL Institute of Child Health, London, UK; Department of Neurological Surgery, Columbia University Medical Center, New York, New York; Division of Pediatric Neurosurgery, Department of Neurosurgery, Miami Children's Hospital, University of Miami/Miller School of Medicine, Miami, Florida; Department of Neurosurgery, Stanford University Medical Center, Palo Alto, California; Department of Neurological Surgery, Weill Medical College of Cornell University and Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Neurosurgery, Children's Hospital Alabama, Birmingham, Alabama; Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Pathology; Department of Neurosurgery; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Department of Histopathology, Great Ormond Street Hospital, NHS Trust, London, UK; Morgan Adams Foundation Pediatric Brain Tumor Research Program; Pediatric Neurosurgery, Children's Hospital Colorado; and Adult and Child Center for Health Outcomes Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
J Neuropathol Exp Neurol. 2017 Sep 1;76(9):779-788. doi: 10.1093/jnen/nlx061.
Pediatric adamantinomatous craniopharyngioma (ACP) is a highly solid and cystic tumor, often causing substantial damage to critical neuroendocrine structures such as the hypothalamus, pituitary gland, and optic apparatus. Paracrine signaling mechanisms driving tumor behavior have been hypothesized, with IL-6R overexpression identified as a potential therapeutic target. To identify potential novel therapies, we characterized inflammatory and immunomodulatory factors in ACP cyst fluid and solid tumor components. Cytometric bead analysis revealed a highly pro-inflammatory cytokine pattern in fluid from ACP compared to fluids from another cystic pediatric brain tumor, pilocytic astrocytoma. Cytokines and chemokines with particularly elevated concentrations in ACPs were IL-6, CXCL1 (GRO), CXCL8 (IL-8) and the immunosuppressive cytokine IL-10. These data were concordant with solid tumor compartment transcriptomic data from a larger cohort of ACPs, other pediatric brain tumors and normal brain. The majority of receptors for these cytokines and chemokines were also over-expressed in ACPs. In addition to IL-10, the established immunosuppressive factor IDO-1 was overexpressed by ACPs at the mRNA and protein levels. These data indicate that ACP cyst fluids and solid tumor components are characterized by an inflammatory cytokine and chemokine expression pattern. Further study regarding selective cytokine blockade may inform novel therapeutic interventions.
小儿成釉细胞瘤型颅咽管瘤（ACP）是一种实性和囊性程度都很高的肿瘤，常对关键神经内分泌结构如下丘脑、垂体和视器造成严重损害。已经有人提出旁分泌信号机制驱动肿瘤行为，其中白细胞介素-6受体（IL-6R）过表达被确定为一个潜在的治疗靶点。为了确定潜在的新疗法，我们对ACP囊液和实体瘤成分中的炎症和免疫调节因子进行了特征分析。细胞计数微珠分析显示，与另一种小儿囊性脑肿瘤——毛细胞型星形细胞瘤的囊液相比，ACP囊液呈现出高度促炎的细胞因子模式。在ACP中浓度特别升高的细胞因子和趋化因子有IL-6、CXCL1（生长调节致癌基因α，GRO）、CXCL8（白细胞介素-8，IL-8）以及免疫抑制细胞因子IL-10。这些数据与来自更大队列的ACP、其他小儿脑肿瘤和正常脑的实体瘤区室转录组数据一致。这些细胞因子和趋化因子的大多数受体在ACP中也过度表达。除了IL-10，已确定的免疫抑制因子吲哚胺2,3-双加氧酶1（IDO-1）在ACP的mRNA和蛋白质水平上均过度表达。这些数据表明，ACP囊液和实体瘤成分具有炎症细胞因子和趋化因子表达模式的特征。关于选择性细胞因子阻断的进一步研究可能为新的治疗干预提供依据。
