TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche.
TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche.
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DOI：
10.1158/0008-5472.can-08-1748
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发表时间：
2008-12
期刊：
影响因子：
11.2
通讯作者：
Masayoshi Yamamoto;H. Kikuchi;M. Ohta;Toshiki Kawabata;Y. Hiramatsu;K. Kondo;Megumi Baba;K. Kamiya;Tatsuo Tanaka;M. Kitagawa;H. Konno
中科院分区：
文献类型：
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作者：
Masayoshi Yamamoto;H. Kikuchi;M. Ohta;Toshiki Kawabata;Y. Hiramatsu;K. Kondo;Megumi Baba;K. Kamiya;Tatsuo Tanaka;M. Kitagawa;H. Konno
本研究的目的是研究TSU 68 [（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; SU 6668]，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（FGFR 1）的抑制剂，对结肠癌肝转移的作用，并检验TSU 68在转移形成之前调节肝脏中的微环境的假设。首先，我们将高转移性人结肠癌TK-4原位植入裸鼠的盲肠壁中，然后每天两次给予TSU 68（400 mg/kg/d）或溶媒。与对照组相比，TSU 68治疗5周可显著抑制肝转移（P<0.001）。接下来，我们使用微阵列分析了转移前肝脏的基因表达谱。微阵列和定量逆转录PCR分析表明，趋化因子CXCL 1的mRNA水平显着增加，在荷瘤小鼠与非荷瘤小鼠相比。此外，CXCL 1的表达显着降低TSU 68治疗。原位肿瘤与异位肿瘤相比，CXCR 2主要在肿瘤细胞上表达。TSU 68治疗组转移前肝脏中的迁移性中性粒细胞数量显著减少（P<0.001）。TSU 68可显著降低门静脉白细胞介素-12（IL-12）p40的表达（P=0.02）。用中和抗体阻断CXCR 2和IL-12 p40显著抑制肝转移。这些结果表明，CXCL 1/CXCR 2轴是重要的癌症转移和TSU 68可能通过抑制炎症反应，这可能是一种替代机制，用于抗血管生成剂调节转移前的小生境在靶器官。
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.