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TSU68 Prevents Liver Metastasis of Colon Cancer Xenografts by Modulating the Premetastatic Niche

¹ Second Department of Surgery, ² Department of Endoscopic and Photodynamic Medicine, and ³ Department of Biochemistry 1, Hamamatsu University School of Medicine, Hamamatsu, Japan

Requests for reprints: Masayoshi Yamamoto, Second Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. Phone: 81-53-435-2279; Fax: 81-53-435-2273; E-mail: ma-yama{at}hama-med.ac.jp.

Key Words: antiangiogenesis • TSU68 • liver metastasis • CXCL1 • premetastatic niche

The aim of this study was to investigate the inhibitory effect of TSU68 [(Z)-5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-propanoic acid; SU6668], an inhibitor of vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis, and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. First, we implanted the highly metastatic human colon cancer TK-4 orthotopically into the cecal walls of nude mice, followed by twice-daily administration of TSU68 (400 mg/kg/d) or vehicle. Five weeks of treatment with TSU68 significantly inhibited liver metastasis compared with the control group (P < 0.001). Next, we analyzed the gene expression profile in premetastatic liver using microarrays. Microarray and quantitative reverse transcription-PCR analysis showed that mRNA levels for the chemokine CXCL1 were significantly increased in tumor-bearing mice compared with non–tumor-bearing mice. Moreover, CXCL1 expression was significantly decreased by TSU68 treatment. CXCR2 expression was detected predominantly on tumor cells in orthotopic tumors compared with ectopic tumors. The number of migrating neutrophils in premetastatic liver was significantly decreased in the TSU68-treated group (P < 0.001). The amount of interleukin-12 (IL-12) p40 in the portal vein was significantly decreased by TSU68 (P = 0.02). Blockade of both CXCR2 and IL-12 p40 with a neutralizing antibody significantly inhibited liver metastasis. These results suggest that the CXCL1/CXCR2 axis is important in cancer metastasis and that TSU68 may modulate the premetastatic niche in the target organ through suppression of the inflammatory response, which might be an alternative mechanism used by antiangiogenic agents. [Cancer Res 2008;68(23):9754–62]

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