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

ABSTRACT: 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.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.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.These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

SUBMITTER: Walters MJ

PROVIDER: S-EPMC3950859 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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

Walters M J MJ Ebsworth K K Berahovich R D RD Penfold M E T ME Liu S-C SC Al Omran R R Kioi M M Chernikova S B SB Tseng D D Mulkearns-Hubert E E EE Sinyuk M M Ransohoff R M RM Lathia J D JD Karamchandani J J Kohrt H E K HE Zhang P P Powers J P JP Jaen J C JC Schall T J TJ Merchant M M Recht L L Brown J M JM

British journal of cancer 20140114 5

<h4>Background</h4>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.<h4>Methods</h4>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 exp ...[more]

PMID: 24423923

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Project description:ObjectiveAs craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period.Methods and materialsOur study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed.ResultsAmong the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %).ConclusionCSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.

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

Publications

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

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