Abstract
The chemokine CXCL12/stromal cell-derived factor-1 and its receptor CXCR4 play a major role in tumor invasion, proliferation, and metastasis. Recently, CXCR7 was identified as a novel, alternate receptor for CXCL12 and CXCL11/I-TAC. Because both chemokines are expressed abundantly in human astrocytomas and glioblastomas, we investigated the occurrence and function of both receptors in astroglial tumors. In situ, CXCR7 is highly expressed on tumor endothelial, microglial, and glioma cells whereas CXCR4 has a much more restricted localization; CXCL12 is often colocalized with CXCR7. CXCR7 transcription in tumor homogenates increased with malignancy. In vitro, CXCR7 was highly expressed in all glioma cell lines investigated whereas CXCR4 was only scarcely transcribed on one of eight lines. In contrast, a tumor stem-like cell line preferentially expressed CXCR4 which diminished upon differentiation, whereas CXCR7 increased drastically. Stimulation of CXCR7-positive glioma cells (CXCR4- and CXCR3-negative) by CXCL12 induced transient phosphorylation of extracellular signal-regulated kinases Erk1/2, indicating that the receptor is functionally active. The phosphoinositide-specific phospholipase C inhibitor U73122 effectively inhibited Erk activation and suggests that the mitogen-activated protein kinase pathway is activated indirectly. Whereas proliferation and migration were little influenced, chemokine stimulation prevented camptothecin- and temozolomide-induced apoptosis. The selective CXCR7 antagonist CCX733 reduced the antiapoptotic effects of CXCL12 as shown by nuclear (Nicoletti) staining, caspase-3/7 activity assays, and cleavage of poly(ADP-ribose) polymerase-1. Thus, CXCR7 is a functional receptor for CXCL12 in astrocytomas/glioblastomas and mediates resistance to drug-induced apoptosis. Whereas CXCR7 is found on "differentiated" glioma cells, the alternate receptor CXCR4 is also localized on glioma stem-like cells.
Highlights
Chemokines, a group of small (8–15 kDa) chemotactic cytokines, and their receptors have been discovered as essential mediators of leukocyte migration in the immune system
We investigated the expression of the chemokine receptors, CXCR7 and CXCR4, as well as their ligands, CXCL12 and CXCL11, in malignant and nonmalignant brain samples by quantitative reverse transcription-PCR (RT-PCR) and immunohistochemistry (Fig. 1)
Whereas CXCL12 is often produced in the pseudopalisading cells and the proliferating microvessels [29], CXCR4 expression is found on tumor endothelial and tumor cells, often in areas of necrosis and angiogenesis [3, 29]; probably due to CXCR4 induction by hypoxia [29]
Summary
Chemokines, a group of small (8–15 kDa) chemotactic cytokines, and their receptors have been discovered as essential mediators of leukocyte migration in the immune system. They play a critical role in tumor initiation, promotion, progression, and metastasis [1]. The chemokine CXCL12 (or stromal cell–derived factor-1) seems to be of particular importance in tumor biology, especially in tumor metastasis. The CXCL12/stromal cell–derived factor-1–CXCR4 axis promotes paracrine tumor growth, tumor cell invasiveness, and tumor angiogenesis [3,4,5,6]. Aside from CXCL12, CXCR7 binds with 10-fold lower affinity CXCL11/I-TAC (IFN-inducible T cell α chemoattractant) which is a ligand for CXCR3 (that is targeted by CXCL9/Mig and CXCL10/IP-10)
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