The Chemokine Receptor CXCR7 Is Highly Expressed in Human Glioma Cells and Mediates Antiapoptotic Effects

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 druginduced apoptosis. Whereas CXCR7 is found on "differentiated" glioma cells, the alternate receptor CXCR4 is also localized on glioma stem-like cells. Cancer Res; 70(8); 3299-308. ©2010 AACR.

Expression of Chemokines and Chemokine Receptors in Brain Tumor Tissue Derived Cells

“…It has previously been reported by Hattermann et al that both CXCR4 and CXCR7 are expressed in astrocytomas/glioblastomas but CXCR4 is found on stemlike cells whereas CXCR7 detected on tumor-infiltrating microglial cells. They concluded that CXCR4 is likely to contribute to the recruitment of tumor stem like cells while CXCR7 seems to inhibit the apoptosis of glioma cells (Hattermann et al, 2010).…”

The presumed atypical chemokine receptor CXCR7 signals through Gi/o proteins in primary rodent astrocytes and human glioma cells

“…The human glioma cell lines, U343 and A764, were propagated in 90% DMEM (Lonzan) and 10% fetal calf serum (FCS; Hattermann et al, 2010). Primary astrocytic cultures and glioma cell cultures were switched to serum-free N2-medium 24 h and 6 h before experiments, respectively, and additionally treated with the following substances as specified in the text: SDF-1a (Millipore, Billerica, MA), I-TAC (Biozol, Eching, Germany); FGF-2 (Peprotech, Rocky Hill, NJ); AMD3100 (dissolved in water; Sigma-Aldrich, St. Louis, MO), CCX771 (dissolved in DMSO; ChemoCentryx, Mountain View, CA), U73122, U73343 (both Merck, Darmstadt, Germany), PTX (Merck).…”

“…CXCR7 expression increases in human astrocytoma tissue and is largely confined to GFAP-expressing cells (Hattermann et al, 2010). Likewise, several human astroglioma cell lines express detectable levels of CXCR7, but not of CXCR4 (Hattermann et al, 2010).…”

“…Likewise, several human astroglioma cell lines express detectable levels of CXCR7, but not of CXCR4 (Hattermann et al, 2010). To assess whether CXCR7 is also coupled to G i/o proteins in malignant astroglial cells, we examined the effects of PTX on SDF-1-induced cell signaling in the CXCR7-posi- tive, CXCR4-negative human glioma cell lines, A764 and U343 (Hattermann et al, 2010).…”

“…A more recent work provided evidence for the increased expression of CXCR7 in high-grade astrocytomas and further revealed that CXCR7 expression prevails over that of CXCR4 in various human glioma cell lines (Hattermann et al, 2010). The subsequent analysis of two of these cell lines, i.e.…”