Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival.
OBJECTIVE
CXCR4 is implicated in the growth, metastasis, and angiogenesis of malignant tumors. We investigated the potential role of CXCR4 in human gliomas.


METHODS
The expression of CXCR4 messenger ribonucleic acid and protein by human glioma cell lines was examined by reverse-transcriptase polymerase chain reaction and immunocytochemistry analysis. Tumor cell chemotaxis and production of vascular endothelial growth factor induced by the CXCR4 ligand SDF-1beta were measured. Xenograft models were used for evaluation of glioma cell tumorigenesis. CXCR4 expression by xenografted tumors and primary human glioma specimens were evaluated for CXCR4 protein expression. The relationship between CXCR4 expression and patient survival was analyzed. A synthetic lipoxygenase inhibitor, Nordy, was tested for its effects on glioma cell expression and function of CXCR4, as well as on glioma cell tumorigenicity.


RESULTS
CXCR4 expression correlated directly with the degree of malignancy of the human glioma cell lines and primary tumors. Activation of CXCR4 induced tumor cell chemotaxis and increased production of vascular endothelial growth factor. Glioma cells expressing higher levels of CXCR4 formed more rapidly growing and lethal tumors in nude mice. Primary human glioma specimens expressing CXCR4 contained high-density microvessels. Patients with CXCR4-positive gliomas had poorer prognosis after surgery. The lipoxygenase inhibitor Nordy diminished CXCR4 expression by glioma cell lines in vitro and reduced their tumorigenicity in nude mice.


CONCLUSIONS
The level of CXCR4 expression seems to correlate with the degree of malignancy of human gliomas and may contribute to their rapid growth.
Bian
Xiu-wu
XW
Institute of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China. bianxiuwu@263.net
Yang
Shi-xin
SX
Chen
Jian-hong
JH
Ping
Yi-fang
YF
Zhou
Xiang-dong
XD
Wang
Qing-liang
QL
Jiang
Xue-feng
XF
Gong
Wanghua
W
Xiao
Hua-liang
HL
Du
Lin-lin
LL
Chen
Zi-qiang
ZQ
Zhao
Wen
W
Shi
Jing-quan
JQ
Wang
Ji Ming
JM
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015996:Survival Rate / Q000639:trends; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D019718:Receptors, CXCR4