This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yasumoto, K. Articles by Saiki, I. Search for Related Content PubMed PubMed Citation Articles by Yasumoto, K. Articles by Saiki, I.

Role of the CXCL12/CXCR4 Axis in Peritoneal Carcinomatosis of Gastric Cancer

¹ Division of Surgical Oncology, Cancer Research Institute, Kanazawa University; ² Kanazawa Medical Center, Kanazawa, Japan; ³ Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine and the ⁴ 21st Century Center of Excellence Program, University of Toyama, Toyama, Japan; and ⁵ Department of Microbiology and Solution Oriented Research for Science and Technology, Kinki University School of Medicine, Osaka, Japan

Requests for reprints: Kazuo Yasumoto, Division of Surgical Oncology, Cancer Research Institute, Kanazawa University, 920-0934 Kanazawa, Japan. E-mail: yasu3578{at}kenroku.kunazawa-u.ac.jp.

Peritoneal carcinomatosis is a frequent cause of death in patients with advanced gastric carcinoma. Because chemokines are now considered to play an important role in the metastasis of various malignancies, we hypothesized that they may be involved in the development of peritoneal carcinomatosis by gastric carcinoma. Human gastric carcinoma cell lines, which were all highly efficient in generating malignant ascites in nude mice upon i.p. inoculation, selectively expressed CXCR4 mRNA and protein. In particular, NUGC4 cells expressed CXCR4 mRNA at high levels and showed vigorous migratory responses to its ligand CXCL12. CXCL12 enhanced proliferation and rapid increases in phosphorylation of protein kinase B/Akt and extracellular signal-regulated kinase of NUGC4 cells. We also showed that AMD3100 (a specific CXCR4 antagonist) effectively reduced tumor growth and ascitic fluid formation in nude mice inoculated with NUGC4 cells. Additionally, we examined human clinical samples. Malignant ascitic fluids from patients with peritoneal carcinomatosis contained high concentrations of CXCL12 (4.67 ng/mL). Moreover, immunohistochemical analysis showed that 22 of 33 primary gastric tumors with peritoneal metastasis were positive for CXCR4 expression (67%), whereas only 4 of 16 with other distant metastasis were positive (25%). Notably, 22 of 26 CXCR4-expressing primary tumors developed peritoneal metastases (85%). CXCR4 positivity of primary gastric carcinomas significantly correlated with the development of peritoneal carcinomatosis (P < 0.001). Collectively, our results strongly suggest that the CXCR4/CXC12 axis plays an important role in the development of peritoneal carcinomatosis from gastric carcinoma. Thus, CXCR4 may be a potential therapeutic target for peritoneal carcinomatosis of gastric carcinoma. (Cancer Res 2006; 66(4): 2181-7)

This article has been cited by other articles:

				V. Levina, B. M. Nolen, A. M. Marrangoni, P. Cheng, J. R. Marks, M. J. Szczepanski, M. E. Szajnik, E. Gorelik, and A. E. Lokshin Role of Eotaxin-1 Signaling in Ovarian Cancer Clin. Cancer Res., April 15, 2009; 15(8): 2647 - 2656. [Abstract] [Full Text] [PDF]

				D. Wong and W. Korz Translating an Antagonist of Chemokine Receptor CXCR4: From Bench to Bedside Clin. Cancer Res., December 15, 2008; 14(24): 7975 - 7980. [Abstract] [Full Text] [PDF]

				C.-T. Tan, C.-Y. Chu, Y.-C. Lu, C.-C. Chang, B.-R. Lin, H.-H. Wu, H.-L. Liu, S.-T. Cha, E. Prakash, J.-Y. Ko, et al. CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway Carcinogenesis, August 1, 2008; 29(8): 1519 - 1527. [Abstract] [Full Text] [PDF]

				S. Bakalian, J.-C. Marshall, P. Logan, D. Faingold, S. Maloney, S. Di Cesare, C. Martins, B. F. Fernandes, and M. N. Burnier Jr. Molecular Pathways Mediating Liver Metastasis in Patients with Uveal Melanoma Clin. Cancer Res., February 15, 2008; 14(4): 951 - 956. [Abstract] [Full Text] [PDF]

				S. Hojo, K. Koizumi, K. Tsuneyama, Y. Arita, Z. Cui, K. Shinohara, T. Minami, I. Hashimoto, T. Nakayama, H. Sakurai, et al. High-Level Expression of Chemokine CXCL16 by Tumor Cells Correlates with a Good Prognosis and Increased Tumor-Infiltrating Lymphocytes in Colorectal Cancer Cancer Res., May 15, 2007; 67(10): 4725 - 4731. [Abstract] [Full Text] [PDF]

				I. Kryczek, S. Wei, E. Keller, R. Liu, and W. Zou Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis Am J Physiol Cell Physiol, March 1, 2007; 292(3): C987 - C995. [Abstract] [Full Text] [PDF]

				CXCR4 in Peritoneal Carcinomatosis of Gastric Carcinoma Cancer Res., April 1, 2006; 66(7): 3957 - 3957. [Full Text] [PDF]