gms | German Medical Science

Objective: The development of resistance to temozolomide (TMZ) as the gold standard of GBM therapy through subsequent tumor recurrence remains still an unsolved problem. CXCR2/CXCL2/CXCL8 signaling pathway has been shown to be altered by TMZ in vitro1. Thus, the aim of our study was to investigate the potential role of this pathway comparing the primary and recurrent tumor of the same patient after TMZ therapy.

Methods: Retrospective GBM tumor samples of 40 matched patients with primary and recurrent GBM were obtained after surgery. All patients received primary surgery and radiochemotherapy. They were divided into two groups early recurrence (2.5-9 months) and late recurrence (≥9 months). FFPE sections of the tumors were stained for microglia/macrophages, vessels, VEGF as well as CXCL2, CXCL8 and their receptor CXCR2. Student’s t-test and one-way ANOVA with Bonferroni correction were applied to compare the groups.

Results: Regardless of the groups, patients showed a significantly higher infiltration of Iba -1⁺ cells in the primary compared to the recurrent tumor (586±373 vs. 311±112cells/mm², p=0.001). Furthermore, a very high infiltration (>800cells/mm²) correlated with early recurrence. The vessel count and area were comparable in primary and recurrent GBM and in both groups without any significant difference. Interestingly, the percentage of CXCR2⁺ vessels was higher in the recurrent GBM tumor samples in both early and late recurrence. Moreover, patients with early recurrence had a significantly lower expression of CXCL2 in the recurrent tumor (-47%±37.7%, p=0.002). There was no difference between the primary and recurrent tumors in the late recurrence group. 40% of the patients expressed CXCL8 in the primary tumors whereas it was expressed of more than 60% in the recurrent tumors. VEGF was heterogeneously expressed in both groups in primary and recurrent tumor samples.

Conclusion: Infiltration of Iba1⁺ cells correlated with the early recurrence in glioblastoma multiforme and thus might lead to tumor progression. CXCL2 possibly plays an important role in angiogenesis in primary GBM whereas it is likely that CXCL8 takes on the role of CXCL2 in recurrent GBM. Further investigations especially on the angiogenic potential of the CXCR2/CXCL2/CXCL8 signaling pathway are needed to better understand the importance of this pathway in GBM recurrence.