CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients. Issue 17 (November 2015)

• Record Type: Journal Article
• Authors: Sand, L.G.L.; Scotlandi, K.; Berghuis, D.; Snaar-Jagalska, B.E.; Picci, P.; Schmidt, T.; Szuhai, K.; Hogendoorn, P.C.W.
• Is Part Of: European journal of cancer. Volume 51:Issue 17(2015:Nov.)
• Page Start: 2624
• Page End: 2633
• Publication Date: 2015-11
• Subjects: Splice variant -- Tumour microenvironment -- Biomarker -- Molecular targeted therapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.08.020
• Languages: English
• ISSNs: 0959-8049

Abstract

Highlights: CXCR7, CXCR4, CXCL12, CXCL14 and CXCR4 isoforms are expressed in Ewing sarcoma. CXCR4-1/CXCR4-2 isoform ratio and CXCL14 and CXCR7 associate with improved survival. CXCR4 and CXCL12 mRNA expression are not associated with survival in Ewing sarcoma. Factors mitigating CXCR4 activation predict better clinical outcomes. Abstract: Purpose: Ewing sarcoma (EWS) is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. Our goal was to identify novel predictive biomarkers for these patients, focusing on chemokines, specifically genes involved in the CXCR4-pathway because of their established role in metastasis and tumour growth. Methods: Total RNA isolated from therapy-naïve tumour samples ( n = 18; panel I) and cell lines ( n = 21) was used to study expression of CXCR4-pathway related genes and CXCR4 splice variants (CXCR4-2: Small and CXCR4-1: Large) by RT-Q-PCR. Expression levels were correlated to overall survival (OS) and event free survival (EFS). Study results were validated in an independent series of 26 tumour samples (panel II) from therapy-naïve tumour samples. Results: CXCL12, CXCR4, CXCR7 and CXCL14 were expressed and high CXCR7 and CXCL14 expression showed a positive correlation with EFS and OS and a negative correlation with metastasis development. Both splice variants CXCR4 were expressed in cell lines and tumour samples and CXCR4-1/CXCR4-2 ratio was significantly higher in tumour samples compared to cell lines and correlated with an improved EFS and OS. The results from the test panel were validated in an independent sample panel. Conclusions: We identified a set of genes involved in CXCR4 signalling that may be used as a marker to predict survival and metastasis development in Ewing sarcoma.