RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth

被引:75
作者
Solga, Anne C. [1 ]
Pong, Winnie W. [1 ]
Kim, Keun-Young [2 ]
Cimino, Patrick J. [3 ]
Toonen, Joseph A. [1 ]
Walker, Jason [4 ]
Wylie, Todd [4 ]
Magrini, Vincent [4 ]
Griffith, Malachi [4 ]
Griffith, Obi L. [4 ]
Ly, Amy [4 ]
Ellisman, Mark H. [2 ]
Mardis, Elaine R. [4 ]
Gutmann, David H. [1 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, San Diego, CA 92103 USA
[3] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63110 USA
来源
NEOPLASIA | 2015年 / 17卷 / 10期
基金
美国国家卫生研究院;
关键词
HUMAN-BRAIN-TUMORS; OPTIC-GLIOMA; MOUSE MODEL; IN-VITRO; DIFFERENTIAL EXPRESSION; PILOCYTIC ASTROCYTOMA; CELL-DIFFERENTIATION; INDUCED ARTHRITIS; BREAST-CARCINOMA; SUPPRESSOR GENE;
D O I
10.1016/j.neo.2015.10.002
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mousemodel of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated thatmicroglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an importantmicroglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.
引用
收藏
页码:776 / 788
页数:13
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