Yamamoto Masayoshi, Kikuchi Hirotoshi, Ohta Manabu, Kawabata Toshiki, Hiramatsu Yoshihiro, Kondo Kenji, Baba Megumi, Kamiya Kinji, Tanaka Tatsuo, Kitagawa Masatoshi, Konno Hiroyuki
Second Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Cancer Res. 2008 Dec 1;68(23):9754-62. doi: 10.1158/0008-5472.CAN-08-1748.
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 beta, 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.
本研究旨在探讨血管内皮生长因子受体2、血小板衍生生长因子受体β和成纤维细胞生长因子受体1（FGFR1）的抑制剂TSU68[（Z）-5-[(1,2-二氢-2-氧代-3H-吲哚-3-亚基)甲基]-2,4-二甲基-1H-吡咯-3-丙酸；SU6668]对结肠癌肝转移的抑制作用，并验证TSU68在转移形成前调节肝脏微环境的假说。首先，我们将高转移性人结肠癌TK-4原位植入裸鼠盲肠壁，随后每日两次给予TSU68（400mg/kg/d）或赋形剂。与对照组相比，TSU68治疗5周显著抑制了肝转移（P<0.001）。接下来，我们使用微阵列分析转移前肝脏中的基因表达谱。微阵列和定量逆转录-PCR分析表明，与无肿瘤小鼠相比，荷瘤小鼠趋化因子CXCL1的mRNA水平显著升高。此外，TSU68治疗显著降低了CXCL1的表达。与异位肿瘤相比，原位肿瘤中CXCR2表达主要在肿瘤细胞上检测到。TSU68治疗组转移前肝脏中迁移的中性粒细胞数量显著减少（P<0.001）。TSU68使门静脉中白细胞介素-12（IL-12）p40的量显著减少（P=0.02）。用中和抗体阻断CXCR2和IL-12 p40均显著抑制了肝转移。这些结果表明，CXCL1/CXCR2轴在癌症转移中很重要；TSU68可能通过抑制炎症反应来调节靶器官中的转移前生态位，这可能是抗血管生成药物使用的另一种机制。
