There is increasing evidence that chemokines and chemokine receptors are causally involved in the metastasis of cancer. Little is known about the possible role of chemokine receptors in the metastasis of gastric cancer. The aim of this study was to investigate the expression of chemokine receptors and their prognostic role in patients with gastric cancer.
We screened the expression of CCR and CXCR chemokine receptors in 12 gastric cancer cell lines using the semi-quantitative RT-PCR. The expression of CCR4, one of the most commonly expressed chemokines, was confirmed using Western blot and flow cytometry analysis of 8 gastric cancer cell lines. The function of CCR4 was examined using migration and proliferation assays. Then the migratory response of CCR4 was blocked using blocking antibodies. Finally, the clinical significance of the chemokine receptors was explored using tissue microarray methods and immunohistochemical staining of specimens from 753 gastric cancer patients.
We found that 6 out of 8 (75.0%) gastric carcinoma cell lines expressed a functional CCR4 for its ligand, chemokine CCL17, as demonstrated by the migration assays, and the migration was inhibited by anti-CCR4 antibodies. The clinical samples evaluated by immunohistochemical assay of tissue microarrays showed that CCR4-positive carcinoma cells were detected in 128 of 753 (17.0%) cases. In addition, there was a significant difference in recurrences between the CCR4-positive and -negative cases (P = 0.009). The patients with CCR4-positive tumors had significantly poorer prognosis than did those with CCR4-negative tumors (5-year survival rate; 71.6% versus 82.5%, respectively, P = 0.008).
These results suggest that CCR4 and its ligands were associated with increased tumor recurrence and impaired overall survival in patients with gastric cancer.
Functioning CCR4 was expressed and associated with disease recurrence in patients with gastric cancer. These results suggest that CCR4 and its ligand are associated with metastasis and a poor prognosis in patients with gastric cancer.
From the *Center for Gastric Cancer, National Cancer Center, 809 Madu1-dong, Ilsandong-gu, Goyang-si, Gyeonggi-do, South Korea; †Department of Pharmacology, Seoul National University College of Medicine, Seoul, South Korea; ‡Center for Clinical Trial, National Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; and §Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Authors Jun Ho Lee and Young-Suk Cho contributed equally to this work.
This study was supported by Grant No. NCC 0710411-1.
Corresponding Author: Jae Moon Bae, MD, PhD, FACS, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 135-710, South Korea. Phone: 82-2-3410-0252. Fax: 82-2-3410-6981. E-mail: email@example.com, firstname.lastname@example.org.