Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer

Abstract

Background & Aims: Gastric cancer is one of the major cancers worldwide. Expression profiling has proven useful in delineating novel prognostic markers in various cancer types. We previously analyzed gene-expression patterns in 90 gastric adenocarcinomas by using complementary DNA microarrays and prioritized a list of genes whose expression levels predict patient outcome. Methods: We identified a specific gene of interest, chemokine (C-C motif) ligand 18 (CCL18), on the basis of a high absolute standardized log Cox hazard ratio, a high variance in expression among all tumor samples, and putative biologic function. Detailed analysis of CCL18 expression with clinicopathologic and survival data was performed (n = 89). Quantitative reverse-transcription polymerase chain reaction was used to verify the microarray expression data and was further applied to analyze an independent cohort of tumor samples (n = 59). The cellular source of CCL18 was determined with immunohistochemistry and in situ hybridization. Results: High CCL18 expression levels were associated with prolonged overall (P = 0.001; hazard ratio, 0.586) and disease-free (P = 0.002; hazard ratio, 0.416) patient survival in the array-based data set by univariate analysis. The observations were confirmed in an independent set of 59 patients by using quantitative reverse-transcription polymerase chain reaction. In multivariate analysis, tumor stage and CCL18 levels were independent prognostic factors for predicting both overall and disease-free survival. We found that CCL18 was expressed by a subpopulation of tumor-associated macrophages that were preferentially located at the tumor invasion front. Conclusions: Macrophage-derived CCL18 may function as a local antitumor immunomodulator that affects patient outcome. Our study suggests CCL18 as a novel candidate for antitumor therapeutics and risk stratification in gastric cancer patients.