Differential expression of the chemokines GRO-2, GRO-3, and interleukin-8 in colon cancer and their impact on metastatic disease and survival.
OBJECTIVE
Chemotactic cytokines play a role in angiogenesis and attraction of immune cells. However, their contribution to tumor formation remains incompletely understood. In a previous transcriptome study, we identified a family of structurally related chemokines of the CXC-family to be specifically up-regulated in colorectal cancer. The aim of the present study was to investigate the regulation of their expression in colon cancer cells and to test the hypothesis that altered CXC-chemokine expression is related to critical clinical parameters, such as survival or metastasis formation.


METHODS
Expression levels of interleukin-8 (CXCL-8) and growth-related oncogenes 2 and 3 (GRO-2/CXCL-2 and GRO-3/CXCL-3) were quantified using qRT-PCR in 97 patients with completely resected colon carcinoma and correlated with clinical parameters. Moreover, 16 samples of normal mucosa, nine samples of benign adenoma, and 11 samples of liver metastasis were analyzed. Next, the regulation of chemokine expression in response to various stimuli was tested in colon cancer cell lines (HT29, HCT116, CaCO2).


RESULTS
Expression of GRO-2, GRO-3, and IL-8 was significantly increased in colon cancer as compared to normal colon tissue. Expression of GRO-2 and GRO-3 was already enhanced in premalignant adenomas, and GRO-3 was significantly down-regulated in liver metastasis as compared to the primary tumor. Importantly, expression of GRO-3 was significantly higher in patients with local versus systemic disease. Moreover, IL-8 expression was significantly associated to overall post-operative survival. Finally, all chemokines were strongly induced by IL-1alpha in the colon cancer cell lines tested, indicating a potential link to inflammatory processes.


CONCLUSIONS
In accordance with earlier findings, we report here a significantly increased expression of GRO-2, GRO-3, and IL-8 in colon carcinoma as compared to normal tissue. Furthermore, GRO-3 was related to metastasis formation, and IL-8 was associated with survival, suggesting a potential predictive power of these markers.
Doll
Dietrich
D
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, München, Germany. dolld@med.uni-marburg.de
Keller
Larissa
L
Maak
Matthias
M
Boulesteix
Anne-Laure
AL
Siewert
Jörg R
JR
Holzmann
Bernhard
B
Janssen
Klaus-Peter
KP
D045744:Cell Line, Tumor; D054426:Chemokine CXCL2 / Q000235:genetics* / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016019:Survival Analysis
C499706:CXCL2 protein, human; C499707:CXCL3 protein, human; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D016209:Interleukin-8