PMID- 22159219
OWN - NLM
STAT- MEDLINE
DCOM- 20120612
LR  - 20220310
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 33
IP  - 2
DP  - 2012 Feb
TI  - A dialog between glioma and microglia that promotes tumor invasiveness through 
      the CCL2/CCR2/interleukin-6 axis.
PG  - 312-9
LID - 10.1093/carcin/bgr289 [doi]
AB  - Glioma cells in situ are surrounded by microglia, suggesting the potential of 
      glioma-microglia interactions to produce various outcomes. As chemokines are 
      important mediators of cell-cell communication, we sought first to identify 
      commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage 
      chemoattractant protein-1) messenger RNA to be expressed by the majority of 
      glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which 
      was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which 
      has low basal level of CCL2, to investigate the hypothesis that glioma-secreted 
      CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 
      12-fold elevation of CCL2 have similar growth rate and invasive capacity as 
      vector controls when cultured in isolation. However, in coculture with microglia 
      in a three-dimensional collagen gel matrix, the invasiveness of 
      CCL2-overexpressing clones was increased. Gene array analyses were then 
      undertaken and they revealed that interleukin (IL)-6 was consistently increased 
      in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when 
      these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the 
      microglia-stimulated glioma invasiveness. Finally, we found that human glioma 
      specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ 
      cells. This study has uncovered a mechanism by which glioma cells exploit 
      microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon 
      CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The 
      CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable 
      malignant gliomas.
FAU - Zhang, Jing
AU  - Zhang J
AD  - Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of 
      Calgary, Calgary, Alberta T2N 4N1, Canada.
FAU - Sarkar, Susobhan
AU  - Sarkar S
FAU - Cua, Rowena
AU  - Cua R
FAU - Zhou, Yan
AU  - Zhou Y
FAU - Hader, Walter
AU  - Hader W
FAU - Yong, V Wee
AU  - Yong VW
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111208
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Antigens, CD)
RN  - 0 (Antigens, Differentiation, Myelomonocytic)
RN  - 0 (CCL2 protein, human)
RN  - 0 (CCR2 protein, human)
RN  - 0 (CD68 antigen, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (FGF7 protein, human)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, CCR2)
RN  - 126469-10-1 (Fibroblast Growth Factor 7)
SB  - IM
MH  - Antibodies, Neutralizing
MH  - Antigens, CD/genetics/metabolism
MH  - Antigens, Differentiation, Myelomonocytic/genetics/metabolism
MH  - Cell Communication/*physiology
MH  - Cell Line, Tumor
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Chemokines/genetics/metabolism
MH  - Coculture Techniques
MH  - Fibroblast Growth Factor 7/metabolism
MH  - Glioma/genetics/metabolism/*pathology
MH  - Humans
MH  - Interleukin-6/antagonists & inhibitors/genetics/*metabolism
MH  - Microglia/metabolism/*pathology
MH  - Neoplasm Invasiveness
MH  - Oligonucleotide Array Sequence Analysis/methods
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptors, CCR2/genetics/*metabolism
MH  - Tumor Microenvironment
EDAT- 2011/12/14 06:00
MHDA- 2012/06/13 06:00
CRDT- 2011/12/14 06:00
PHST- 2011/12/14 06:00 [entrez]
PHST- 2011/12/14 06:00 [pubmed]
PHST- 2012/06/13 06:00 [medline]
AID - bgr289 [pii]
AID - 10.1093/carcin/bgr289 [doi]
PST - ppublish
SO  - Carcinogenesis. 2012 Feb;33(2):312-9. doi: 10.1093/carcin/bgr289. Epub 2011 Dec 
      8.