1. ¹Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2. ²Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3. ³Department of Clinical Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4. ⁴Kitano Hospital Medical Institute, Osaka, Japan

Correspondence: Professor MM Taketo, Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan. E-mail: taketo@mfour.med.kyoto-u.ac.jp

⁵These authors contributed equally to this paper.

Received 25 September 2006; Revised 14 November 2006; Accepted 1 December 2006; Published online 5 February 2007.

Abstract

Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA ('DLD-1-CXCR3'), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (P<0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.