Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2

Shoji, Tuyoshi; Konno, Hiroyuki; Tanaka, Tatsuo; Sakaguchi, Takanori; Sunayama, Kenichi; Baba, Megumi; Kamiya, Kinji; Ohta, Michio; Kaneko, Takeshi; Igarashi, Akira

doi:10.1016/s0304-3835(02)00108-8

Cited by 10 publications

(6 citation statements)

References 20 publications

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Section: Discussionmentioning

confidence: 52%

“…In a previous study, we confirmed that TK-4 expresses VEGF-A, cyclooxygenase (COX)-1, COX-2 (24), and the active form of matrix metalloproteinase-2 (42). COX-2 expression was significantly up-regulated in the orthotopically implanted tumors and was positively correlated with the number of liver metastases (24). Kaplan and colleagues (23) have shown that VEGF and placental growth factor derived from tumor cells up-regulate fibronectin in resident fibroblasts, which results in the activation of VEGFR1-positive hematopoietic bone marrow progenitor cells in premetastatic organs, providing a permissive niche for incoming tumor cells.…”

Section: Discussionmentioning

confidence: 52%

“…TK-001, used as another model of colon carcinoma, has no liver metastasis ability. TK-4 was implanted orthotopically into cecal walls by suturing 120-mg tumor pieces with 6-0 Polysorb (Tyco Healthcare) or transplanting them s.c. into the right axillary regions of 6-wk-old male BALB/c nu/nu mice (Clea Japan), as previously described (24)(25)(26)(27).…”

Section: Animals and Tumor Modelsmentioning

confidence: 99%

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

Yamamoto¹,

Kikuchi²,

Ohta³

et al. 2008

Cancer Research

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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, plateletderived growth factor receptor B, 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 tumorbearing 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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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 52%

Section: Animals and Tumor Modelsmentioning

confidence: 99%

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

Yamamoto¹,

Kikuchi²,

Ohta³

et al. 2008

Cancer Research

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“…To assess the local invasion and metastatic potential of sprouty-2 up-regulated HCT-116 cells, we performed cecal orthotopic tumor implantations (Shoji et al, 2003). Mice were anesthetized with ketamine (70 mg/kg body wt) and Xylazine (7 mg/kg body wt).…”

Section: Methodsmentioning

confidence: 99%

Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas

et al. 2010

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Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/ERK pathways. Sprouty is down-regulated in breast, prostate and liver cancers and appears to function as a tumor suppressor. The role of Sprouty in colonic neoplasia, however, has not been investigated. Sprouty-2 protein and mRNA transcripts were significantly up-regulated in human colonic adenocarcinomas. Strikingly, the c-Met receptor was also upregulated in tumors with increased sprouty-2. To delineate a potential causal relationship between sprouty-2 and c-Met, K-ras mutant HCT-116 colon cancer cells were transduced with purified TAT-sprouty-2 protein or stably transfected with full-length human sprouty-2 gene. Sprouty-2 up-regulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants demonstrated strong up-regulation of c-Met protein and mRNA transcripts and hepatocyte growth factor stimulated ERK and Akt phosphorylation and enhanced cell migration and invasion. In contrast, knockdown of c-Met by siRNA significantly decreased cell proliferation, migration and invasion in sprouty-2 transfectants. Further, knockdown of sprouty-2 by siRNA in parental HT-29 and LS-174T colon cancer cells also decreased cell invasion. Sprouty-2 transfectants formed significantly larger tumor xenografts and demonstrated increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to liver from cecal orthotopic implants suggesting sprouty-2 might also enhance metastatic signals. Thus in colon cancer sprouty functions as an oncogene and its effects are mediated in part by c-Met up-regulation.

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“…It has been extensively documented that overexpression of COX-2 is implicated in various forms of human cancers such as cancer of the lung [26], breast [27], colorectal [28], prostate [29], head and neck [30] and others [31,32]. In particular, increased COX-2 expression has been brought in connection with tumour metastasis in colon cancer [33] where aberrant COX-2 expression was shown to correlate with carcinogenesis in more than 80% of colorectal cancers [34]. In animal models COX-2 expression was found to be sufficient to induce tumourigenesis [35].…”

Section: The Cox Pathwaymentioning

confidence: 99%

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

Hyde

Missailidis

2009

International Immunopharmacology

143

101

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Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention.

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Orthotopic implantation of a colon cancer xenograft induces high expression of cyclooxygenase-2

Cited by 10 publications

References 20 publications

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

Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

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