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¹ Department of Surgery and Surgical Basic Science and ² Department of Bioorganic Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

Requests for Reprints:Ryuichiro Doi, Department of Surgery and Surgical Basic Science, Kyoto University, 54-Shogoin Kawara-cho, Sakyo, Kyoto 606-8507, Japan. Phone: 81-75-751-3671; Fax: 81-75-751-3219. E-mail: doir{at}kuhp.kyoto-u.ac.jp

The stromal cell-derived factor-1 (SDF-1)/CXCR4 system is implicated in various instances of cell migration in mammals, including the migration of lymphocytes and the formation of metastases. We have recently synthesized a potent novel CXCR4 antagonist, TN14003. The purpose of this study was to investigate the role of SDF-1/CXCR4 axis in the pancreatic cancer metastasis via cell migration and invasion, and the inhibitory effect of TN14003 on pancreatic cancer cell metastasis. The expression of CXCR4 was detected in six pancreatic cancer cell lines by Western blotting and immunocytochemistry. In migration and invasion assays, SDF-1 stimulated both migration and invasion of cancer cells in a dose-dependent manner. The maximal effect of SDF-1 was observed at 100 ng/ml. SDF-1-induced migration and invasion of cancer cells were completely blocked by 100 nM TN14003. The stimulatory effect of SDF-1 on cancer migration and the inhibitory effect of TN14003 were mediated via the alteration in phosphorylation of mitogen-activated protein kinases. Treatment of cancer cells with 100 ng/ml SDF-1 resulted in a significant increase of actin polymerization, which was reduced by 100 nM TN14003. SDF-1 enhanced cancer cell adhesion to laminin, which was not reversed by TN14003. Taken together, SDF-1/CXCR4 axis is involved in pancreatic cancer metastasis through migration and invasion. The small molecule antagonists against CXCR4 such as TN14003 might be an effective anti-metastatic agent for pancreatic cancer.

Key Words: CXCR4 • SDF • migration • invasion • receptor antagonist

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Grant support: Grant-in-Aid for Scientific Research (#15390395) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Note: T. Mori and R. Doi contributed equally.

Received 8/11/03; revised 10/13/03; accepted 10/16/03.