Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

Oki, Masayuki; Yamamoto, Hiroyuki; Taniguchi, Hiroaki; Adachi, Yasushi; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.3748/wjg.14.5650

Cited by 65 publications

(48 citation statements)

References 24 publications

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“…In addition, c-Ret and EphA4 were also activated in human colon cancer tissue. Overexpression of ErbB2, FGFR1, FGFR2a, c-Ret and EphA4 have already been reported in various cancers including colon cancer (14,(35)(36)(37)(38)(39). These reports support our result on the various RTKs detected from the protein array used in this study.…”

Section: Discussionsupporting

confidence: 82%

The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

Morishita

Gong²,

Nomura³

et al. 2010

Int J Oncol

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Abstract. Several studies have reported that activated receptor tyrosine kinases (RTKs) are highly expressed in colon cancer and may promote tumor growth and survival. However, there is little information available as to the function and signaling of RTKs in colon cancers. In the present study, we performed protein array technology to determine the expression status of various RTKs that are activated in colon cancer compared to normal colonic cells and tissues. Of the 42 different phospho-RTKs, 5 (ErbB2, FGFR1, FGFR2a, FGFR3 and MSPR) were activated in Caco-2, SW480, WiDr, Lovo colon cancer cell lines and cancerous tissues. In order to determine the effect of inhibition of RTKs, especially ErbB2, athymic nude mice bearing xenograft tumors were treated with the ErbB2-targeting drug trastuzumab alone, or in combination with 5-Fluorouracil (5-FU). Similar to the treatment of 5-FU alone, trastuzumab suppressed the growth of colon cancer. Combination therapy of trastuzumab and 5-FU inhibited tumor growth significantly compared to the treatment of 5-FU alone or trastuzumab alone. In addition, xenograft tumors were also analyzed by phospho-MAPK protein array. The activity of Akt3/PKBÁ was inhibited with 5-FU alone and trastuzumab, indicating that trastuzumab may inhibit colon cancer growth through ErbB2-Akt3/PKBÁ signaling. These data demonstrate that ErbB2 could be an important candidate for colon cancer therapy and the addition of trastuzumab to 5-FU therapy might augment the clinical response in colon cancer patients. Therefore, the analysis of phospho-RTK expression by protein array as a useful tool might identify novel therapies for individual patients with colon cancer.

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Section: Discussionsupporting

confidence: 82%

The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

Morishita

Gong²,

Nomura³

et al. 2010

Int J Oncol

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“…EphA4 was activated in all gastric cancer tissues and other cell lines except MKN1 used in the present study. Overexpression of EGFR, ErbB2, FGFR1, FGFR2·, EphA4 has been already reported in gastric cancer (26,(28)(29)(30)(31). The previous report support our results on the various RTKs activated in gastric cancer derived from the protein array used in this study.…”

Section: Discussionsupporting

confidence: 81%

Use of protein array to investigate receptor tyrosine kinases activated in gastric cancer

Gong

Morishita²,

Kurokohchi³

et al. 2009

Int J Oncol

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Abstract. Our study used protein array technology to analyze the expression status of various activated receptor tyrosine kinases (RTKs) in gastric carcinoma; then, we sought to discover an effective therapeutic receptor tyrosine kinase for this disease and investigated the anti-tumor mechanism of the therapeutic RTK. In addition to the expressions of activated RTKs in human gastric cancer and adjacent normal mucosa, the expression of activated RTKs in gastric cancer cell lines, MKN74, MKN45, MKN7 and MKN1, were also studied. The RTKs activated in gastric cancer tissue are EGFR, ErbB2, FGFR1, FGFR2· insulin R, and EphA4. Among the RTKs activated in gastric cancer tissues, EGFR and ErbB2 were also activated in all gastric cell lines examined in this study. A subsequent in vitro experiment using subcutaneous gastric cancer-bearing athymic nude mice demonstrated that the ErbB2-targeting drug trastuzumab markedly suppressed the growth of gastric cancer. Moreover, using an angiogenesis protein array, the expressions of Ang I, FGF-·, FGF-ß TGF-ß and IL-8 in MKN74 xenograft tumors were found to be significantly reduced by treatment with trastuzumab, indicating that trastuzumab may inhibit the expression of angiogenic molecules in MKN74 cells in vivo. These data suggest that ErbB2 is activated in gastric cancer, and the ErbB2-targeting drug trastuzumab may be related to the reduction of Ang 1, FGF·, FGFß, TGF· and IL-8.

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“…In gastric cancer, a previous study reported the presence of FGFR1 amplifications in 12 (50%) of the 24 cases and FGFR1 protein was overexpressed in 37 (61%) of the 61 specimens on immunohistochemical analysis using a monoclonal antibody that differed from the one used in the present study. However, that study reported no significant correlation between FGFR1 expression and clinicopathological characteristics (17). To the best of our knowledge, the present study is the first to demonstrate that the high expression of FGFR1 is associated with poor survival in gastric cancer.…”

Section: Discussionmentioning

confidence: 58%

“…Overexpression of these FGFRs in gastric cancer was reported by a few small studies (16)(17)(18)(19). In this study, we aimed to investigate the correlations of FGFR1-4 immunohistochemical expression with clinicopathological characteristics and outcomes in gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer

Murase

Inokuchi

Takagi

et al. 2014

Molecular and Clinical Oncology

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Abstract. The overexpression of fibroblast growth factor receptor (FGFR) 2 is an established prognostic factor and treatment target in gastric cancer. However, the roles of other FGFRs have not been fully elucidated. In this study, we investigated the correlations of the expression of FGFR1-4 with clinicopathological characteristics and outcomes in gastric cancer. Tumor samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy between 2003 and 2007. The expression of each FGFR was measured in the tumors by immunohistochemical analysis. The overexpression of FGFR1, FGFR2 or FGFR4 was found to be significantly associated with tumor progression, including depth of invasion, lymph node metastasis, pathological stage and distant metastasis or recurrent disease. Patients exhibiting overexpression of FGFR1, FGFR2 or FGFR4 had a significantly poorer disease-specific survival (DSS; P<0.001, P=0.008 and P<0.001, respectively). Moreover, the co-overexpression of all three FGFRs was significantly associated with a poorer DSS compared to the expression of none or only one of the FGFRs (P<0.001 and P=0.001, respectively) and it was found to be an independent prognostic factor (HR=1.71, 95% CI: 1.02-2.85, P=0.041). In conclusion, high expression of FGFR1, FGFR2 or FGFR4 was associated with tumor progression and poor survival in patients with gastric cancer. Similar to FGFR2, FGFR1 and FGFR4 may be considered as prognostic factors and treatment targets in gastric cancer.

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Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers

Cited by 65 publications

References 24 publications

The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer

Use of protein array to investigate receptor tyrosine kinases activated in gastric cancer

Prognostic significance of the co-overexpression of fibroblast growth factor receptors 1, 2 and 4 in gastric cancer

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