TY - JOUR
T1 - F11R Is a Novel Monocyte Prognostic Biomarker for Malignant Glioma
AU - Pong, Winnie W.
AU - Walker, Jason
AU - Wylie, Todd
AU - Magrini, Vincent
AU - Luo, Jingqin
AU - Emnett, Ryan J.
AU - Choi, Jaebok
AU - Cooper, Matthew L.
AU - Griffith, Malachi
AU - Griffith, Obi L.
AU - Rubin, Joshua B.
AU - Fuller, Gregory N.
AU - Piwnica-Worms, David
AU - Feng, Xi
AU - Hambardzumyan, Dolores
AU - DiPersio, John F.
AU - Mardis, Elaine R.
AU - Gutmann, David H.
N1 - Funding Information:
The authors have read the journal's policy and have the following potential conflicts; there are no direct conflicts of interest. Dr. Pong reports grants from the W. M. Keck Foundation during the conduct of the study. Dr. Feng reports personal fees from National Cancer Institute and Cleveland Clinic, and non-financial support from University of Michigan outside the submitted work. Dr. Mardis reports personal fees from Pacific Biosciences Inc and from Illumina Inc, and other from Life Technologies, outside the submitted work. Dr. Gutmann reports grants from National Cancer Institute and from National Institutes of Health during the conduct of the study; personal fees from Biomarin, outside the submitted work; In addition, Dr. Gutmann has Neurofibromatosis type 1 patents. None of these organizations were involved in the study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication. This does not alter their adherence to all the PLOS ONE policies on sharing data and materials.
PY - 2013/10/11
Y1 - 2013/10/11
N2 - Objective:Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome.Methods:High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM.Results:We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype.Significance:These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention.
AB - Objective:Brain tumors (gliomas) contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM) biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome.Methods:High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO) database was queried to determine the prognostic value of identified microglia biomarkers in human GBM.Results:We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype.Significance:These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention.
UR - http://www.scopus.com/inward/record.url?scp=84885411121&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0077571
DO - 10.1371/journal.pone.0077571
M3 - Article
C2 - 24147027
AN - SCOPUS:84885411121
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 10
M1 - e77571
ER -