Overexpression of Transforming Growth Factor-β1 in Scirrhous Carcinoma of the Stomach Correlates with Decreased Survival

Kinugasa, Shoichi; Abe, Shogo; Tachibana, Mitsuo; Hishikawa, Yoshitaka; Yoshimura, Hiroshi; Monden, Naomi; Dhar, Dipok Kumar; Nagasue, Naofumi; Nagaoka, Saburo

doi:10.1159/000011916

Cited by 32 publications

(27 citation statements)

References 19 publications

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“…Though examples exist in which a cell's proliferative response to TGF-b switches from inhibition to stimulation in parallel with tumor progression (Hsu et al, 1994;Matsuzaki et al, 2000), attenuation of the autocrine loop by decreased expression of the TbRII receptor, leaving intact paracrine signaling to host cells is a frequently-implicated paradigm. Consistent with this formulation of the role of TGF-b in cancer, an association between increased production of TGF-b by tumors and worse clinical outcome has been noted for many epithelial cancers (Gorsch et al, 1992;Takanami et al, 1994;Friedman et al, 1995;Kinugasa et al, 1998;WikstroÈ m et al, 1998;Maehara et al, 1999;Saito et al, 1999). The experiments outlined in this study were designed to contrast in vivo and in vitro consequences of altered tumor cell TGF-b expression and responsiveness, and distinguish between autocrine and paracrine e ects.…”

Section: Discussionmentioning

confidence: 56%

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

et al. 2002

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To characterize the impact of increased production of TGF-b in a xenograft model of human breast cancer, TGF-b-responsive MDA-231 cells were genetically modi®ed by stable transfection so as to increase their production of active TGF-b1. Compared with control cells, cells that produced increased amounts of TGF-b proliferated in vitro more slowly. In vivo, however, tumors derived from these cells exhibited increased proliferation and grew at an accelerated pace. To evaluate the role of autocrine TGF-b signaling, cells were also transfected with a dominant-negative truncated type II TGF-b receptor (TbRII). Disruption of autocrine TGF-b signaling in the TGF-b-overexpressing cells reduced their in vivo growth rate. Co-inoculation of Matrigel with the TGF-b-overexpressing cells expressing the truncated TbRII compensated for their diminished in vivo growth capacity, compared with the TGF-b-overexpressing cells with an intact autocrine loop. Tissue invasion by the tumor was a distinctive feature of the TGF-b-overexpressing cells, whether or not the autocrine loop was intact. Furthermore, tumors derived from TGFb-overexpressing cells, irrespective of the status of the autocrine TGF-b-signaling pathway, had a higher incidence of lung metastasis. Consistent with the suggestion that TGF-b's enhancement of invasion and metastasis is paracrine-based, we observed no signi®cant di erences among the cell clones in an in vitro invasion assay. Thus, in this experimental model system in vitro assays of cell proliferation and invasion do not accurately re¯ect in vivo observations, perhaps due to autocrine and paracrine e ects of TGF-b that in¯uence the important in vivo-based phenomena of tumor growth, invasion, and metastasis.

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Section: Discussionmentioning

confidence: 56%

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

et al. 2002

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“…Although TGF-b produced by cancer cells and/or by cancer-associated fibroblasts enhances the fibrosis, the role of TGF-b in the development of diffuse-type gastric carcinoma still remains controversial (Mizoi et al, 1993;Mishra et al, 2005). Either increased or decreased survival in diffuse-type carcinoma patients were reported to correlate with the expression of TGF-b (Kinugasa et al, 1998;Vagenas et al, 2007). However, our present findings suggest that TGF-b suppresses the progression of tumor by induction of the differentiation of CICs of this type of cancer.…”

Section: Reduction Of Sp Cells In Gastric Cancer By Tgf-b S Ehata Et Almentioning

confidence: 99%

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

et al. 2010

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Stem cells in normal tissues and cancer-initiating cells (CICs) are known to be enriched in side population (SP) cells. However, the factors responsible for the regulation of expression of ABCG2, involved in efflux of dyes, in SP cells have not been fully investigated. Here, we characterized the SP cells within diffuse-type gastric carcinoma, and examined the effects of transforming growth factor-b (TGF-b) on SP cells. Diffuse-type gastric carcinoma cells established from four independent patients universally contained SP cells between 1 and 4% of total cells, which displayed greater tumorigenicity than non-SP cells did. TGF-b repressed the transcription of ABCG2 through direct binding of Smad2/3 to its promoter/enhancer, and the number of SP cells and the tumor-forming ability of cancer cells were decreased by TGF-b, although ABCG2 is not directly involved in the tumor-forming ability of SP cells. Cancer cells from metastatic site expressed much higher levels of ABCG2 and included a greater percentage of SP cells than parental cancer cells did. SP cells are thus responsible for the progression of diffuse-type gastric carcinoma, and TGF-b negatively contributes to maintain the CICs within the cancer.

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“…Overexpression of TGF-b is reported to be correlated with poor prognosis of gastric tumours (Saito et al, 2000), especially scirrhous gastric carcinoma (Kinugasa et al, 1998), suggesting that TGF-b signalling might have an important role in the progression of scirrhous gastric cancer cells (Inoue et al, 1997;Kinugasa et al, 1998;Kawajiri et al, 2008). Therefore, inhibition of TGF-b signalling in scirrhous gastric carcinoma may yield beneficial effects through inhibition of invasion and metastasis of cancer.…”

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confidence: 99%

Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

et al. 2010

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BACKGROUND: Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-b (TGF-b) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-b receptor (TbR) phosphorylation inhibitor on the invasiveness of gastric cancer cells. METHODS: Four gastric cancer cell lines, including two scirrhous-type cell lines and two non-scirrhous-type cell lines, were used. A TbR type I (TbR-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of TbR-I. We investigated the expression levels of TbR and phospho-Smad2, and the effects of TGF-b in the presence or absence of Ki26894 on Smad2 phosphorylation, invasion, migration, epithelial-to-mesenchymal transition (EMT), Ras homologue gene family member A (RhoA), ZO-2, myosin, and E-cadherin expression of gastric cancer cells. RESULTS: TbR-I, TbR-II, and phospho-Smad2 expressions were found in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. Ki26894 decreased Smad2 phosphorylation induced by TGF-b1 in scirrhous gastric cancer cells. Transforming growth factor-b1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-b1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-b1 decreased ZO-2 and E-cadherin expression in scirrhous gastric cancer cells. Interestingly, Ki26894 inhibited these characteristics in scirrhous gastric cancer cells. In contrast, non-scirrhous gastric cancer cells were not affected by TGF-b1 or Ki26894 treatment. CONCLUSION: A TbR-I kinase inhibitor decreases the invasiveness and EMT of scirrhous gastric cancer cells. Ki26894 is therefore considered to be a promising therapeutic compound for the metastasis of scirrhous gastric carcinoma.

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Overexpression of Transforming Growth Factor-β1 in Scirrhous Carcinoma of the Stomach Correlates with Decreased Survival

Cited by 32 publications

References 19 publications

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects

Transforming growth factor-β decreases the cancer-initiating cell population within diffuse-type gastric carcinoma cells

Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

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