CXCR4 Is a Major Chemokine Receptor on Glioma Cells and Mediates Their Survival

Abstract

Chemokines were described originally in the context of providing migrational cues for leukocytes. They are now known to have broader activities, including those that favor tumor growth. We addressed whether and which chemokines may be important promoters of the growth of the incurable brain neoplasm, malignant gliomas. Analyses of 16 human glioma lines for the expression of chemokine receptors belonging to the CXCR and CCR series revealed low to negligible levels of all receptors, with the exception of CXCR4 that was expressed by 13 of 16 lines. All six resected human glioma specimens showed similarly high CXCR4 expression. The 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. Furthermore, SDF-1 induced the phosphorylation of Akt (protein kinase B), a kinase associated with survival, and prevented the apoptosis of glioma cells when serum was withdrawn from the culture medium. SDF-1 also mediated glioma chemotaxis, in accordance with this better known role of chemokines. We conclude that glioma cells express a predominant chemokine receptor, CXCR4, and that this functions to regulate survival in part through activating pathways such as Akt.

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

“…44 CXCL12 has also been involved in the survival of glioma cells by activating the Akt pathway. 45 These findings identify CXCR4 -CXCL12 as potential prognostic biomarkers for GBMs, which display heterogeneity in regard to invasiveness, angiogenesis, and extent of necrosis. Studies analyzing the cellular and genetic changes which occur during the genesis and progression of human gliomas have demonstrated the overexpression of CXCR4 in GBM tissue as compared with normal brain tissue.…”

Constitutive CXCL12 Expression Induces Anoikis in Colorectal Carcinoma Cells

“…In fact, recent reports suggest that exogenous CXCL12 stimulation can enhance cell survival. [33][34][35] It is tempting to speculate that exogenous stimulation of CXCR4-expressing cells with CXCL12 is analogous to endocrine signaling in vivo. In this case, sensing of ectopic CXCL12 by CXCR4-expressing/CXCL12-null carcinoma cells would enhance their survival and metastasis.…”

Chemokines in cancer related inflammation

“…Leukemic cells expressing CXCR4 home to bone marrow and access to niches where stromal cells secrete CXCL12 [73]. In glioblastoma, several CXC receptors have been reported, with CXCR4 being the most frequent and being associated with aggressive disease and poor patient survival [91][92][93].…”