PMID- 21324923
OWN - NLM
STAT- MEDLINE
DCOM- 20110711
LR  - 20220409
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 71
IP  - 7
DP  - 2011 Apr 1
TI  - COX-2 blockade suppresses gliomagenesis by inhibiting myeloid-derived suppressor 
      cells.
PG  - 2664-74
LID - 10.1158/0008-5472.CAN-10-3055 [doi]
AB  - Epidemiologic studies have highlighted associations between the regular use of 
      nonsteroidal anti-inflammatory drugs (NSAID) and reduced glioma risks in humans. 
      Most NSAIDs function as COX-2 inhibitors that prevent production of prostaglandin 
      E(2) (PGE(2)). Because PGE(2) induces expansion of myeloid-derived suppressor cells 
      (MDSC), we hypothesized that COX-2 blockade would suppress gliomagenesis by 
      inhibiting MDSC development and accumulation in the tumor microenvironment (TME). 
      In mouse models of glioma, treatment with the COX-2 inhibitors acetylsalicylic 
      acid (ASA) or celecoxib inhibited systemic PGE(2) production and delayed glioma 
      development. ASA treatment also reduced the MDSC-attracting chemokine CCL2 (C-C 
      motif ligand 2) in the TME along with numbers of CD11b(+)Ly6G(hi)Ly6C(lo) 
      granulocytic MDSCs in both the bone marrow and the TME. In support of this 
      evidence that COX-2 blockade blocked systemic development of MDSCs and their 
      CCL2-mediated accumulation in the TME, there were defects in these processes in 
      glioma-bearing Cox2-deficient and Ccl2-deficient mice. Conversely, these mice or 
      ASA-treated wild-type mice displayed enhanced expression of CXCL10 (C-X-C motif 
      chemokine 10) and infiltration of cytotoxic T lymphocytes (CTL) in the TME, 
      consistent with a relief of MDSC-mediated immunosuppression. Antibody-mediated 
      depletion of MDSCs delayed glioma growth in association with an increase in 
      CXCL10 and CTLs in the TME, underscoring a critical role for MDSCs in glioma 
      development. Finally, Cxcl10-deficient mice exhibited reduced CTL infiltration of 
      tumors, establishing that CXCL10 limited this pathway of immunosuppression. Taken 
      together, our findings show that the COX-2 pathway promotes gliomagenesis by 
      directly supporting systemic development of MDSCs and their accumulation in the 
      TME, where they limit CTL infiltration.
FAU - Fujita, Mitsugu
AU  - Fujita M
AD  - Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, 
      Pennsylvania, USA.
FAU - Kohanbash, Gary
AU  - Kohanbash G
FAU - Fellows-Mayle, Wendy
AU  - Fellows-Mayle W
FAU - Hamilton, Ronald L
AU  - Hamilton RL
FAU - Komohara, Yoshihiro
AU  - Komohara Y
FAU - Decker, Stacy A
AU  - Decker SA
FAU - Ohlfest, John R
AU  - Ohlfest JR
FAU - Okada, Hideho
AU  - Okada H
LA  - eng
GR  - R21 NS055738/NS/NINDS NIH HHS/United States
GR  - P01 NS040923/NS/NINDS NIH HHS/United States
GR  - 2P01NS40923/NS/NINDS NIH HHS/United States
GR  - 1R01NS055140/NS/NINDS NIH HHS/United States
GR  - P01 NS040923-08/NS/NINDS NIH HHS/United States
GR  - 1R21NS055738/NS/NINDS NIH HHS/United States
GR  - P01 CA132714/CA/NCI NIH HHS/United States
GR  - P3CA047904/CA/NCI NIH HHS/United States
GR  - P01 CA132714-02/CA/NCI NIH HHS/United States
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - R01 NS055140/NS/NINDS NIH HHS/United States
GR  - 1P01CA132714/CA/NCI NIH HHS/United States
GR  - R21 NS055738-02/NS/NINDS NIH HHS/United States
GR  - P30 CA047904-22/CA/NCI NIH HHS/United States
GR  - R01 NS055140-03/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 - 20110215
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL10)
RN  - 0 (Cyclooxygenase 2 Inhibitors)
RN  - 0 (Lysosomal-Associated Membrane Protein 1)
RN  - 0 (Pyrazoles)
RN  - 0 (Sulfonamides)
RN  - EC 1.14.99.1 (Cyclooxygenase 2)
RN  - JCX84Q7J1L (Celecoxib)
RN  - K7Q1JQR04M (Dinoprostone)
RN  - R16CO5Y76E (Aspirin)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - Anti-Inflammatory Agents, Non-Steroidal/*pharmacology
MH  - Aspirin/pharmacology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Celecoxib
MH  - Chemokine CCL2/immunology
MH  - Chemokine CXCL10/immunology
MH  - Cyclooxygenase 2/biosynthesis/genetics
MH  - Cyclooxygenase 2 Inhibitors/*pharmacology
MH  - Dinoprostone/antagonists & inhibitors/biosynthesis
MH  - Female
MH  - Glioma/enzymology/immunology/pathology/*prevention & control
MH  - Lysosomal-Associated Membrane Protein 1/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Myeloid Cells/*drug effects/enzymology/immunology/pathology
MH  - Pyrazoles/pharmacology
MH  - Sulfonamides/pharmacology
MH  - T-Lymphocytes, Cytotoxic/immunology
PMC - PMC3075086
MID - NIHMS273699
EDAT- 2011/02/18 06:00
MHDA- 2011/07/12 06:00
PMCR- 2012/04/01
CRDT- 2011/02/18 06:00
PHST- 2011/02/18 06:00 [entrez]
PHST- 2011/02/18 06:00 [pubmed]
PHST- 2011/07/12 06:00 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - 0008-5472.CAN-10-3055 [pii]
AID - 10.1158/0008-5472.CAN-10-3055 [doi]
PST - ppublish
SO  - Cancer Res. 2011 Apr 1;71(7):2664-74. doi: 10.1158/0008-5472.CAN-10-3055. Epub 
      2011 Feb 15.