Expression of the Chemokine Receptor CXCR4 and Its Ligand Stromal Cell‐Derived Factor 1 in Human Brain Tumors and Their Involvement in Glial Proliferation in Vitro

Abstract

Chemokines are a family of proteins that chemoattract and activate cells by interacting with specific receptors on the surface of their targets. They are grouped into four classes based on the position of key cysteine residues: C, CC, CXC, and CX3C. Stromal cell-derived factor 1 (SDF1), the ligand of the CXCR4 receptor, is a CXC chemokine involved in chemotaxis and brain development that also acts as coreceptor for HIV-1 infection. It has been proposed that CXCR4 is overexpressed and required for proliferation in human brain tumor cells. We previously demonstrated that CXCR4 and SDF1 are expressed in culture of cortical type I rat astrocytes, cortical neurons, and cerebellar granule cells. In this study, we analyzed the expression of CXCR4 and SDF1 in four human brain tumor tissues, showing that CXCR4 is expressed in all tumors analyzed, whereas SDF1 is expressed only in two tumor tissues. We also investigated the possible functions of CXCR4 expressed in rat type I cortical astrocytes, demonstrating that SDF1alpha stimulates the proliferation of these cells in vitro. Moreover, we studied by western blot the intracellular pathway involved in cell proliferation, demonstrating that SDF1alpha induces the ERK1/2 phosphorylation that is reduced by the PD98059 compound, an MEK inhibitor.

SDF1α/CXCR4 Signaling, via ERKs and the Transcription Factor Egr1, Induces Expression of a 67-kDa Form of Glutamic Acid Decarboxylase in Embryonic Hippocampal Neurons

“…Previous cell culture studies have provided evidence that signals from glial cells influence development of the GABAergic phenotype of hippocampal neurons during early postnatal development (52). Although the identity of the glial cell-derived factor is unknown, SDF1␣ is one possibility as it is known to be produced by astrocytes (53,54).…”

Comparative evaluation of survivin, midkine, and CXCR4 promoters for transcriptional targeting of glioma gene therapy

“…However, CXCR-4 has been found to be upregulated on malignant glioma. 9,[23][24][25][26] In a seminal article, Zhou et el., showed that CXCR4 on glioma lines is a signaling receptor in that its agonist, stromal cell-derived factor-1 (SDF-1; CXCL12), produced rapid phosphorylation of mitogen-activated protein kinases. 9 Furthermore, SDF-1 induced the phosphorylation of Akt (protein kinase B), a kinase associated with survival, and prevented the apoptosis of glioma cells.…”

Abnormal production of the TNF-homologue APRIL increases the proliferation of human malignant glioblastoma cell lines via a specific receptor

“…Some cytokines, such as stromal cell-derived factor 1 (SDF-1) (Barbero et al, 2003), epidermal growth factor (EGF) (Held-Feindt et al, 2003) and IL-6 (Goswami et al, 1998), have been reported to be produced and to increase cell proliferation in glioblastoma cell lines. We investigated whether the addition of APRIL affected the secretion of one of these molecules, IL-6.…”