Abstract
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.
Highlights
The idea of targeting angiogenesis to treat tumors was first proposed more than 30 years ago [1]
These results suggest an antimetastatic effect of TSU68 on colon cancer xenografts
We focused on CXCL1, one of the CXC chemokines, the expression level of which was decreased by about a quarter by TSU68 treatment (Fig. 2B), because a number of reports have shown that chemokines are closely related to cancer metastasis [17, 32, 33]
Summary
The idea of targeting angiogenesis to treat tumors was first proposed more than 30 years ago [1]. The original concept of antiangiogenesis was the inhibition of outgrowth of new blood vessels [3]; it became more obvious that bevacizumab may affect the vasculature through various mechanisms: It (a) causes regression of the tumor vasculature, (b) normalizes the tumor vasculature, (c) inhibits the formation of new blood vessels, and (d) prevents recruitment of progenitor cells from the bone marrow [3,4,5,6] Understanding of these detailed mechanisms provided the rationale for combination therapy using antiangiogenic agents and cytotoxic chemotherapy [4, 7]. Receptor tyrosine kinase inhibitors are small, synthetic, selective molecules that have favorable toxicity profiles, do not induce an immune response, and have an ability to inhibit multiple receptors simultaneously [11]
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