A Novel Molecular Targeting Compound as K-samII/FGF-R2 Phosphorylation Inhibitor, Ki23057, for Scirrhous Gastric Cancer

Nakamura, Kazunori; Yashiro, Masakazu; Matsuoka, Tasuku; Tendo, Masashige; Shimizu, Toshiyuki; Miwa, Atsushi; Hirakawa, Kosei

doi:10.1053/j.gastro.2006.08.030

Cited by 67 publications

(46 citation statements)

References 18 publications

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“…We have previously reported that proliferation of DGC cells was stimulated by FGF-7, which is a ligand of FGFR-2, but not by VEGF. Ki23057 blocks the autophosphorylation of fibroblast growth factor receptor 2 and VEGFR-3 (Shimizu et al, 2004;Nakamura et al, 2006). Ki23057 might decrease the growth of DGC tumour by inhibiting the FGFR-2 signalling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Ki23057, a newly developed tyrosine kinase inhibitor, competes with ATP for the binding site in the kinase and therefore blocks the autophosphorylation of VEGFR-3 and fibroblast growth factor receptor 2 (FGFR-2) (Shimizu et al, 2004;Nakamura et al, 2006). The characteristic clinical features of diffuse-type gastric carcinoma (DGC), a diffusely infiltrating type of gastric carcinoma also known as scirrhous gastric carcinoma, include a high frequency of metastasis to the LNs (Hippo et al, 2001;Nakazawa et al, 2003) and to the peritoneum (Yashiro et al, 1996;Takemura et al, 2004;Tendo et al, 2005).…”

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confidence: 99%

“…The characteristic clinical features of diffuse-type gastric carcinoma (DGC), a diffusely infiltrating type of gastric carcinoma also known as scirrhous gastric carcinoma, include a high frequency of metastasis to the LNs (Hippo et al, 2001;Nakazawa et al, 2003) and to the peritoneum (Yashiro et al, 1996;Takemura et al, 2004;Tendo et al, 2005). Although we currently reported the effects of Ki23057 on the peritoneal dissemination of DGC with an amplification of the activated FGF-R2 (K-samII) gene (Shimizu et al, 2004;Nakamura et al, 2006), no candidate agent as VEGFR-3 phosphorylation inhibitor has yet been proposed for the molecular target therapy of LN metastasis. The molecular controls of tumour-induced lymphangiogenesis through the VEGFR-3 signalling system may be targets for novel therapeutics designed to restrict LN metastasis.…”

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Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

et al. 2009

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BACKGROUND: Vascular endothelial growth factor receptor-3 (VEGFR-3) signalling mediates lymphangiogenesis and lymphatic invasion; however, the effect of VEGFR-3 inhibition on the lymph node (LN) metastasis remains unclear. The aim of this study is to clarify the benefit of a VEGFR-3 inhibitor Ki23057 for LN metastasis. METHODS: Ki23057 was administered orally to gastric cancer models created by orthotopic inoculation of diffuse-type gastric cancer cells, OCUM-2MLN. The effects of Ki23057 on lymphatic vessel invasion, lymphatic vessel density, and VEGFR-3 phosphorylation were examined by immunostaining or immunoblotting. RESULTS: Ki23057 inhibited the autophosphorylation of VEGFR-3, with IC 50 values of 4.3 nM in the cell-free kinase assay. Murine gastric cancer models created by the orthotopic inoculation of OCUM-2MLN cells showed the diffusely infiltrating growth and frequently developed LN metastasis. The oral administration of Ki23057 significantly (Po0.01) reduced the size of orthotopic tumours and the number of the metastatic LN in gastric cancer models. The degree of lymphatic invasion and lymphangiogenesis was significantly (Po0.05) lower in the gastric tumours treated by Ki23057. Ki23057 inhibited the phosphorylation of VEGFR-3 of lymphatic endothelial cells in gastric tumours. CONCLUSION: The inhibition of lymphangiogenesis targeting VEGFR-3 phosphorylation is a therapeutic strategy for inhibiting LN metastasis of diffuse-type gastric cancer.

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Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

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“…Ki23057, a newly developed small molecule acting FGFR-2/K-samII inhibitor, is a kinase inhibitor that competes with ATP for the binding site in the kinase [76]. Ki23057 decreases the proliferation of scirrhous cancer cells by inhibiting the phosphorylation of FGFR-2/K-samII, thus resulting in an increase of apoptosis [77]. The oral administration of Ki23057 prolongs the survival of mice with peritoneal metastasis of scirrhous cancer.…”

Section: Therapies To Target the Cancer-stromal Interactionsmentioning

confidence: 99%

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Yashiro

Hirakawa

2010

Cancer Microenvironment

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Fibroblasts play an important role in the progression, growth and spread of gastric cancers. Cancer-stroma interactions have been especially evident in the scirrhous type of gastric carcinoma. Fibroblasts are associated with the cancer progression at the primary and metastatic site. The proliferative and invasive ability of scirrhous gastric cancer cells are closely associated with the growth factors produced by organ-specific fibroblasts. Fibroblasts are therefore a key determinant in the malignant progression of gastric cancer and represent an important target for cancer therapies.

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“…The prognosis of patients with SGC is extremely poor, mostly due to frequent incidence of lymph node metastasis and peritoneal dissemination of cancer cells; therefore, understanding the molecular mechanism underlying these characteristics of SGC for the development of new therapies has become urgent (Ikeguchi et al, 2004;Nakamura et al, 2006).…”

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Direct cancer–stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells

et al. 2009

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BACKGROUND: Scirrhous-type gastric carcinoma (SGC) exhibits an extensive submucosal fibrosis and extremely poor patient prognosis. We investigated the importance of the cancer -stromal interaction in the histogenesis of SGC. METHODS: Gastric fibroblasts NF-25 and intestinal fibroblasts NF-j2 were co-cultured with SGC-derived (HSC-39) or non-SGCderived (HSC-57 and HSC-64) cells. To identify genes that are up-or downregulated in NF-25, complementary DNA (cDNA) microarray analysis was performed. The antibody against vascular-cell adhesion molecule-1 (VCAM-1) was used for cell growth test and immunohistochemistry. Moreover, the impact of interaction with NF-25 fibroblasts on HSC-39 cells was investigated using western blot and reverse transcription-polymerase chain reaction. RESULTS: HSC-39 cells stimulated growth of NF-25 but not NF-j2 when co-cultured. Induction of VCAM-1 in NF-25 fibroblasts was identified, which was specific when co-cultured with HSC-39 but not with non-SGC-derived HSC-57 and HSC-64 cells. Neutralising antibody to VCAM-1 suppressed NF-25 growth in dose-dependent manners. In tissue samples, positive immunoreactivity of VCAM-1 in SGC-derived fibroblasts was significantly higher than that in non-SGC-derived fibroblasts. Furthermore, interaction with NF-25 fibroblasts not only induced the epithelial -mesenchymal transition-like change, but also expressions of matrix metalloproteinaserelated genes in HSC-39 cells. CONCLUSION: Direct interaction between SGC cells and gastric fibroblasts establishes the tumour microenvironment and reinforces the aggressiveness of SGC.

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A Novel Molecular Targeting Compound as K-samII/FGF-R2 Phosphorylation Inhibitor, Ki23057, for Scirrhous Gastric Cancer

Cited by 67 publications

References 18 publications

Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

Effects of VEGFR-3 phosphorylation inhibitor on lymph node metastasis in an orthotopic diffuse-type gastric carcinoma model

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

Direct cancer–stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells

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