Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer.
OBJECTIVE
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.
Leung
Suet Yi
SY
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, China. suetyi@hkucc.hku.hk
Yuen
Siu Tsan
ST
Chu
Kent-Man
KM
Mathy
Jonathan A
JA
Li
Rui
R
Chan
Annie S Y
AS
Law
Simon
S
Wong
John
J
Chen
Xin
X
So
Samuel
S
D000230:Adenocarcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D000465:Algorithms; D018033:Antibodies, Bispecific; D014408:Biomarkers, Tumor / Q000235:genetics; D019742:Chemokines, CC / Q000235:genetics* / Q000276:immunology; D005753:Gastric Mucosa / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D008264:Macrophages / Q000502:physiology; D011379:Prognosis; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology
D018033:Antibodies, Bispecific; D014408:Biomarkers, Tumor; C111792:CCL18 protein, human; D019742:Chemokines, CC