PMID- 27013192 OWN - NLM STAT- MEDLINE DCOM- 20170724 LR - 20181113 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 76 IP - 9 DP - 2016 May 1 TI - CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages. PG - 2552-60 LID - 10.1158/0008-5472.CAN-15-2386 [doi] AB - Current therapies for high-grade gliomas extend survival only modestly. The glioma microenvironment, including glioma-associated microglia/macrophages (GAM), is a potential therapeutic target. The microglia/macrophage cytokine CSF1 and its receptor CSF1R are overexpressed in human high-grade gliomas. To determine whether the other known CSF1R ligand IL34 is expressed in gliomas, we examined expression array data of human high-grade gliomas and performed RT-PCR on glioblastoma sphere-forming cell lines (GSC). Expression microarray analyses indicated that CSF1, but not IL34, is frequently overexpressed in human tumors. We found that while GSCs did express CSF1, most GSC lines did not express detectable levels of IL34 mRNA. We therefore studied the impact of modulating CSF1 levels on gliomagenesis in the context of the GFAP-V12Ha-ras-IRESLacZ (Ras*) model. Csf1 deficiency deterred glioma formation in the Ras* model, whereas CSF1 transgenic overexpression decreased the survival of Ras* mice and promoted the formation of high-grade gliomas. Conversely, CSF1 overexpression increased GAM density, but did not impact GAM polarization state. Regardless of CSF1 expression status, most GAMs were negative for the M2 polarization markers ARG1 and CD206; when present, ARG1(+) and CD206(+) cells were found in regions of peripheral immune cell invasion. Therefore, our findings indicate that CSF1 signaling is oncogenic during gliomagenesis through a mechanism distinct from modulating GAM polarization status. Cancer Res; 76(9); 2552-60. (c)2016 AACR. CI - (c)2016 American Association for Cancer Research. FAU - De, Ishani AU - De I AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Steffen, Megan D AU - Steffen MD AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Clark, Paul A AU - Clark PA AD - Department of Neurological Surgery and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Patros, Clayton J AU - Patros CJ AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Sokn, Emily AU - Sokn E AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Bishop, Stephanie M AU - Bishop SM AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Litscher, Suzanne AU - Litscher S AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Maklakova, Vilena I AU - Maklakova VI AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Kuo, John S AU - Kuo JS AD - Department of Neurological Surgery and Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin. FAU - Rodriguez, Fausto J AU - Rodriguez FJ AD - Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland. FAU - Collier, Lara S AU - Collier LS AD - School of Pharmacy, Carbone Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin. lcollier@wisc.edu. LA - eng GR - UL1 TR000427/TR/NCATS NIH HHS/United States GR - R01 NS075995/NS/NINDS NIH HHS/United States GR - HHSN261201000130C/CA/NCI NIH HHS/United States GR - P30 CA014520/CA/NCI NIH HHS/United States GR - UL1 RR025011/RR/NCRR NIH HHS/United States GR - R01 CA158800/CA/NCI NIH HHS/United States GR - R01 NS085364/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160324 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 81627-83-0 (Macrophage Colony-Stimulating Factor) RN - EC 2.7.10.1 (Receptor, Macrophage Colony-Stimulating Factor) SB - IM MH - Animals MH - Brain Neoplasms/*pathology MH - Cell Line, Tumor MH - Glioma/*pathology MH - Humans MH - Immunohistochemistry MH - Macrophage Colony-Stimulating Factor/*biosynthesis MH - Macrophages/cytology MH - Mice MH - Mice, Transgenic MH - Microglia/cytology MH - Microscopy, Confocal MH - Polymerase Chain Reaction MH - Receptor, Macrophage Colony-Stimulating Factor/metabolism MH - Tissue Array Analysis MH - Up-Regulation PMC - PMC4873447 MID - NIHMS778387 COIS- The authors have no conflict of interests to declare. EDAT- 2016/03/26 06:00 MHDA- 2017/07/25 06:00 PMCR- 2017/05/01 CRDT- 2016/03/26 06:00 PHST- 2015/08/28 00:00 [received] PHST- 2016/02/22 00:00 [accepted] PHST- 2016/03/26 06:00 [entrez] PHST- 2016/03/26 06:00 [pubmed] PHST- 2017/07/25 06:00 [medline] PHST- 2017/05/01 00:00 [pmc-release] AID - 0008-5472.CAN-15-2386 [pii] AID - 10.1158/0008-5472.CAN-15-2386 [doi] PST - ppublish SO - Cancer Res. 2016 May 1;76(9):2552-60. doi: 10.1158/0008-5472.CAN-15-2386. Epub 2016 Mar 24.