Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats

Abstract

Background:In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed.Methods:We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro.Results:CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.Conclusions:These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

Dual Targeting of the Chemokine Receptors CXCR4 and ACKR3 with Novel Engineered Chemokines

“…In 2008, Plerixafor gained Food and Drug Administration approval for mobilization of hematopoietic stem cell transplants in non-Hodgkin lymphoma and multiple myeloma (18), making CXCR4 the second chemokine receptor (in addition to CCR5) to be the target of a marketed drug. Small molecule inhibitors of ACKR3 are extensively studied because of their ability to block tumor reappearance in experimental models of glioblastoma multiforme (19). Finally, chemokine-based inhibitors also show therapeutic promise (20,21); for example, P2G-CXCL12, an antagonist variant of CXCL12, was demonstrated to slow the progression of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (21).…”

Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas

“…Previous results focusing on the expression of both receptors in human GBM indeed yielded an expression of CXCR4 by a subpopulation of GBM cells with stem cell properties (14), whereas the bulk of more differentiated GBM cells express CXCR7 (15,24). Conversely, other studies reported the existence of CXCR4-CXCR7 double-positive cells and showed that this subpopulation might regulate the stem cell phenotype (25), and was able to initiate intracranial tumors in vivo (26). Nevertheless, also CXCR4 and CXCR7 single populations exist and a high level of heterogeneity in both the surface expression and functions of CXCR4 and CXCR7 in primary human GBM cells of the proliferative subclass was determined (26).…”

“…Nevertheless, also CXCR4 and CXCR7 single populations exist and a high level of heterogeneity in both the surface expression and functions of CXCR4 and CXCR7 in primary human GBM cells of the proliferative subclass was determined (26). In addition, GBM primary cell cultures show a heterogeneous cell surface expression of CXCR4 and CXCR7 despite similar levels of corresponding mRNAs (25), and the expression of CXCR4 and CXCR7 is significantly correlated (19).…”

Tumor Microenvironment, Hypoxia, and Stem Cell-Related Radiation Resistance

“…The involvement of the CXCL12-CXCR4/ CXCR7 axis in GSCs radioresistance has been strengthened by the recent observation that CXCR7 blockade after irradiation signifi cantly reduced tumor growth and relapse, and enhanced survival in a xenograft model of glioblastoma, likely affecting GSCs [ 179 ].…”