Novel models for human scirrhous gastric carcinoma <i>in vivo</i>

Takemura, Susumu; Yashiro, Masakazu; Sunami, Takeshi; Tendo, Masashige; Hirakawa, Kosei

doi:10.1111/j.1349-7006.2004.tb02199.x

Cited by 40 publications

(28 citation statements)

References 32 publications

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“…30 31,32 CAF cell lines had been established from the primary tumor site of diffuse/poorly differentiated gastric adenocarcinomas and NF lines from the 'normal' non-neoplastic counterpart (as matched pairs). The procedure is described elsewhere.…”

Section: Immunohistochemistry and Fluorescence Immunohistochemistrymentioning

confidence: 99%

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THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

et al. 2011

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Gastric adenocarcinomas can be divided into two major histological types, the diffuse and intestinal type (Laurén classification). Since they diverge in many clinical and molecular characteristics, it is widely accepted that they represent distinct disease entities that may benefit from different therapeutic approaches. Gene expression profiling studies have identified numerous genes that are differentially expressed between them. However, none of these studies covered the whole transcriptome and the published gene lists reveal little overlap, raising the need for further, more comprehensive analyses. Here, we present the first transcriptome-wide expression profiling study comparing the two types (diffuse n ¼ 19, intestinal n ¼ 24), which identified 41000 genes that are differentially expressed. Among them, thrombospondin 4 (THBS4) showed the strongest correlation to histological type, with vast overexpression in the diffuse type. Quantitative real-time PCR validated this strong overexpression and revealed that intestinal tumors generally lack THBS4 expression. Immunohistochemistry demonstrated THBS4 overexpression on the protein level (n ¼ 10) and localized THBS4 to the stromal aspect. Its expression was primarily observed within the extracellular matrix surrounding the tumor cells, with the highest intensities found in regions of high tumor cell density and invasion. Intestinal tumors and matched non-neoplastic gastric epithelium and stroma did not feature any relevant THBS4 expression in a preliminary selection of analyzed cases (n ¼ 5). Immunohistochemical colocalization and in vitro studies revealed that THBS4 is expressed and secreted by cancer-associated fibroblasts. Furthermore, we show that THBS4 transcription in fibroblasts is stimulated by tumor cells. This study is the first to identify THBS4 as a powerful marker for diffuse-type gastric adenocarcinomas and to provide an initial characterization of its expression in the course of this disease.

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Section: Immunohistochemistry and Fluorescence Immunohistochemistrymentioning

confidence: 99%

“…31,32,34 In vitro, OCUM cells exclusively grow in suspension (single or in cell clusters), whereas MKN-45 cells predominantly grow adherent as mono or multilayers with only few cells being suspended. This behavior is not characteristic for diffuse-type gastric tumors or their cell lines.…”

Section: Thbs4 Expression In Gastric Adenocarcinomamentioning

confidence: 99%

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

et al. 2011

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“…Orthotopic implantation of scirrhous gastric cancer cells in the stomach shows extensive fibrosis with the occasional presence of poorly differentiated adenocarcinoma cells which resembles scirrhous gastric carcinoma [13]. Scirrhous gastric cancer cells increase the proliferation of fibroblasts, but not well-differentiated adenocarcinoma cells [14].…”

Section: Tgfβ From Gastric Cancer Cells Stimulates the Proliferation mentioning

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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“…Human diffuse-type gastric carcinoma cells were cultured as shown in Supplementary Table S1 (Takemura et al, 2004;Yashiro et al, 2009;Yanagihara et al, 1993). Lentivirus vectors were used to generate 2MLN-dnTbRII and control 2MLN-GFP cells as described .…”

Section: Cell Culturementioning

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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Novel models for human scirrhous gastric carcinoma in vivo

Cited by 40 publications

References 32 publications

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling

Cancer–Stromal Interactions in Scirrhous Gastric Carcinoma

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

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