CXCR4: A new player in vestibular schwannoma pathogenesis

// Maria Breun 1 , Alexandra Schwerdtfeger 1 , Donato Daniel Martellotta 1 , Almuth F. Kessler 1 , Jose M. Perez 1 , Camelia M Monoranu 2, 3 , Ralf-Ingo Ernestus 1 , Cordula Matthies 1 , Mario Lohr 1, * and Carsten Hagemann 1, * 1 Department of Neurosurgery, University Hospital Wurzburg, 97080 Wurzburg, Germany 2 Department of Neuropathology, University of Wurzburg, Institute of Pathology, 97080 Wurzburg, Germany 3 Comprehensive Cancer Center (CCC), Mainfranken, Wurzburg * These authors contributed equally to this work Correspondence to: Maria Breun, email: Breun_M@ukw.de Keywords: vestibular schwannoma; CXCR4; CXCL12 chemokine; tumor microenvironment Received: July 12, 2017      Accepted: December 03, 2017      Published: January 10, 2018 ABSTRACT Background : CXCR4 is a chemokine receptor that recruits blood stem cells and increases tumor cell growth and invasiveness. We examined CXCR4 expression in vestibular schwannomas (VS) from patients with and without neurofibromatosis type 2 (NF2) and correlated the levels with the patients’ clinical characteristics. The aim was to determine whether CXCR4 can be used as a prognostic marker and as a target for systemic therapy. Results : Overall, CXCR4 mRNA levels were 4.6-fold higher in VS versus control; the levels were 4.9-fold higher in NF2 patients and 4.2-fold higher in sporadic VS patients. IHC and WB showed heterogeneous protein expression, and CXCR4 was expressed mainly in S100-positive Schwann cells. There was no correlation between the CXCR4 protein levels and tumor extension. However, there was a trend towards correlation between higher expression levels and greater hearing loss. Materials and Methods : CXCR4 mRNA and protein levels were determined in VS samples ( n = 60); of these, 30 samples were from patients with NF2. Healthy nerves from autopsies served as controls. CXCR4 mRNA levels were measured by PCR, and protein levels were measured by immunohistochemistry (IHC) and Western blotting (WB). Tumor extension and hearing loss were categorized according to the Hannover Classification as clinical parameters. Conclusions : CXCR4 mRNA was overexpressed in VS relative to healthy vestibular nerves, and there was a trend towards higher CXCR4 expression levels being correlated with greater functional impairment. Thus, CXCR4 may be a prognostic marker of VS, and CXCR4 inhibition has potential as a systemic approach for the treatment of VS.