Abstract 392: CXCR2 expression in tumor cells is associated with an adverse outcome in a large set of non-small-cell lung cancer (NSCLC)
Authors: Saintigny Pierre , Liu Diane , Lee J. Jack , Ping Yuan , Behrens Carmen , Solis Soto Luisa M. , Heymach John V. , Kim Edward S. , Hong Waun Ki , Kurie Jonathan M. , Wistuba Ignacio I. , Koo Ja Seok 
Published: July 2012

Abstract
Background: CXCR2 plays an important role in inflammation, and stimulation of CXCR2-expressing endothelial cells by ELR+ CXC chemokines promotes angiogenesis. Our goal was to study the expression of CXCR2 by tumor cells and its impact on prognosis in NSCLC. Material and Methods: CXCR2 expression was determined using immunohistochemistry and a large set of tissue microarray including 458 NSCLC. The association between cytoplasmic CXCR2 (cCXCR2) expression in tumor cells and clinico-pathological factors as well as survival was analyzed. Distribution of CXCR2 and its ligands (IL8, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6 and CXCL7) gene expression was studied using publicly available gene expression profiles from 52 NSCLC cell lines (GSE4824) and 444 lung adenocarcinomas (adc) (NCI Director's Challenge). To summarize the effect of CXCR2/CXCR2 ligands biological axis, Principal Component Analysis (PCA) and unsupervised hierarchical clustering were performed using CXCR2 and its ligands gene expression in both cell lines and lung adc. The first Principal Component (PC1) was correlated (Pearson) with the whole genome in 52 NSCLC cell lines. All genes were ranked according to their correlation with PC1, and used for Gene Set Enrichment Analysis (GSEA) “pre-ranked” analysis. Results: Using the median of expression to dichotomize the patients in a high versus low expression group, 238 (52.1%) tumors expressed high cCXCR2. No association was observed with gender, race, smoking habits, histology, and stage. High cCXCR2 was associated with overall survival (Hazard ratio (HR) 1.5696; confidence interval (CI)=1.176-2.096, p-value=0.002) and recurrence-free survival (HR 1.321; CI=1.027-1.698, p-value=0.030) in a univariate Cox proportional hazards (CPH) model. High cCXCR2 remained significant for overall in a multicovariate CPH after adjusting for age, gender, histology, stage, neoadjuvant chemotherapy for overall survival (HR 1.465; CI=1.088-1.972, p-value=0.012) and a trend was observed for recurrence-free survival (HR 1.261; CI=0.973-1.633, p-value=0.080). Gene expression distribution of CXCR2 and its ligands were strikingly similar in cell lines and lung adc. In both cases, hierarchical clustering showed a cluster mostly driven by CXCR2, CXCL5, and CXCL7, representing 20% of the samples. PC1 accounted for 48.25 and 46.15% of the variation of the PCA in cell lines and lung adc respectively. KRAS and NFKB oncogenic pathways were the top 2 gene sets associated with PC1. Using the median as a cutoff, PC1 was associated with a worse overall survival in 444 lung adc (Log-rank P=0.006). Conclusion: cCXCR2 expression in NSCLC tumor cells is frequent and associated with an adverse outcome. CXCR2/CXCR2 ligands biological axis may be associated with an activation of KRAS and NFKB pathways, and a poor prognosis in lung adc. Funding Source: Department of Defense-VITAL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 392. doi:10.1158/1538-7445.AM2011-392