COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer

Möbius, Christian; Stein, Hubert J.; Spiess, C; Becker, Ingrid; Feith, Marcus; Theisen, Jörg; Gais, Peter; Jütting, Uta; Siewert, J. R.

doi:10.1016/j.ejso.2005.01.006

Cited by 53 publications

(47 citation statements)

References 11 publications

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“…In the present study, constitutive overexpression of ING4 significantly up-regulated the expression of p27 and down-regulated the expression of cyclinD1 and SKP2, suggesting that ING4 might inhibit A549 cell proliferation by arresting cell cycle progression in late G1 before pRb hyperphosphorylation. Cox2, a central enzyme in the prostaglandin biosynthetic pathway, plays a key role in the early stages of carcinogenesis by promoting tumor cell proliferation and their resistance to apoptosis, as well as angiogenesis, tumor cell invasion, and setting up of the metastatic process (Möbius et al, 2005;Tzankov et al, 2007). We found that constitutive overexpression of ING4 decreased the expression of Cox2, which might therefore be a pathway through which ING4 exerts its inhibitory action on A549 cell proliferation and tumor growth.…”

Section: Discussionmentioning

confidence: 75%

Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt‐1/β‐Catenin Signaling Pathway

Li¹,

Cai²,

Liang³

et al. 2008

The Anatomical Record

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ING4, as a novel candidate tumor suppressor gene, has been implicated in several human malignances by tumor growth inhibition and apoptosis enhancement. The mechanism of ING4 remains largely unknown. The purpose of this study was to investigate the inhibitory tumor growth effects of ING4 on lung adenocarcinoma, and its mechanism, by ING4 cDNA transduction into A549 cells. Furthermore, the expression level of ING4 in lung adenocarcinoma tissues was examined. The expression of ING4 was markedly reduced in human lung adenocarcinoma tissues. Overexpression of ING4 can induce growth inhibition in A549 cells both in vitro and in vivo, and also induce up-regulation of p27, down-regulation of cyclinD1, SKP2, and Cox2, and inactivation of the Wnt-1/b-catenin pathway. Moreover, overexpression of ING4 can enhance the sensitivity of A549 cells to radiotherapy and chemotherapy. Thus, ING4 may play an inhibitory role on A549 cell proliferation and tumor growth in lung adenocarcinoma by up-regulation or down-regulation of cell proliferation-regulating proteins such as p27, cyclinD1, SKP2, and Cox2 by means of inactivation of Wnt-1/b-catenin signaling.

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Section: Discussionmentioning

confidence: 75%

Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt‐1/β‐Catenin Signaling Pathway

Li¹,

Cai²,

Liang³

et al. 2008

The Anatomical Record

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“…[1][2][3][4][5][6]14,15 Although previous studies established a trend in the metaplasia-dysplasia-carcinoma sequence, none have clearly demonstrated whether high-grade dysplasia is significantly different from metaplasia or lowgrade dysplasia. Our study specifically demonstrates a significant and stepwise increase in microvascular density between Barrett' esophagus, low-grade dysplasia and high-grade dysplasia, which has not been previously shown.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of microvascular density in Barrett's associated neoplasia

et al. 2013

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Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. The aim of this study is to assess the correlation between microvascular density and disease progression of non-dysplastic Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and invasive carcinoma in the superficial aspects of the tissue. Archival histological specimens from two referral centers for Barrett's esophagus and esophageal cancer were selected for review. A total of 160 regions marked according to histological grade were assessed with digitally interactive software to measure microvascular density. This was quantified in three levels: 0-50, 50-100 and 100-150 lm. In the areas of gastric cardia, Barrett's esophagus, low-grade dysplasia, high-grade dysplasia and cancer, microvascular density was significantly different (Po0.0001) among the five groups in the most superficial 150 lm of the mucosa. Furthermore, when examining the pairwise difference between the groups, there was a significant difference between cancer and each of the lower grades of histology (Po0.05) and between high-grade dysplasia and each of the lower grades of histology (Po0.05). These statistically significant differences were preserved in examining the depth at the most superficial 50 lm. We have used digital pathology to demonstrate a significant and stepwise increase in microvascular density, which supports the hypothesis that angiogenesis has a key role in Barrett's carcinogenesis. Furthermore, the differences in the most superficial mucosal layers are consistent with findings of increased vascularity by depth-restricted imaging modalities. Modern Pathology (2013) 26, 125-130; doi:10.1038/modpathol.2012 published online 24 August 2012 Keywords: angiogenesis; Barrett's esophagus; esophageal cancer; microvascular density Angiogenesis has an important role in the carcinogenesis of esophageal adenocarcinoma, however, the diagnostic and prognostic utility of microvascular density counts have not been clinically established. 1,2 Esophageal adenocarcinoma arises from Barrett's esophagus in a metaplasia-dysplasia-carcinoma sequence. Intestinal metaplasia and dysplasia have been studied in terms of microvascular density, and neoangiogenesis is thought to begin in these precursor lesions. [3][4][5][6][7]

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“…21 Cox-2 suppression therapy has been suggested for better prognostic outcomes in Barrett's carcinomas. 43 Upregulation of Cox-2 has been associated with increased proliferation mediated by activation of MAPK pathways, due to acid and bile salt exposure in SEG-1 cells. 22,23 Such proliferation was not seen in the non-neoplastic BAR-T cells.…”

Section: Discussionmentioning

confidence: 99%

“…22,24,40 Increased levels of Cox-2 have been reported in Barrett's tissues 41 and in several cases of esophageal adenocarcinoma, 22,40,[42][43][44] although no causal link has yet been established. Cox-2 expression is generally associated with inflammatory or stress responses.…”

mentioning

confidence: 99%

Repeated exposure to acid and bile selectively induces colonic phenotype expression in a heterogeneous Barrett's epithelial cell line

Bajpai

Liu

Geng

et al. 2008

Laboratory Investigation

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Barrett's epithelium is a precancerous, specialized columnar metaplasia in the distal esophagus. We demonstrate the changes in cellular phenotype in a non-neoplastic Barrett's cell line (BAR-T), following exposure to acid and bile salt, the two important components of gastroesophageal refluxate. Cell phenotypes in BAR-T cell line were quantified by fluorescence-activated cell sorting (FACS) using monoclonal antibodies against markers: cytokeratin 8/18 (CK8/18) for columnar, CK4 for squamous, mAbDas-1 for colonic epithelial cell phenotype and p75NTR for esophageal progenitors. Cells were exposed for 5 min each day to 200 mM glycochenodeoxycholic acid at pH 4, pH 6 and pH 7.4 or only to acid (pH 4) for up to 6 weeks. The BAR-T cell line comprised 35 ± 5.2% CK8/18, 32 ± 3.5% mAbDas-1, 9.5 ± 3% CK4 and 4 ± 2.5% p75NTR-positive cells. Single exposure to acid and or bile did not change cell phenotypes. However, chronic treatment for at least 2 weeks significantly enhanced (Po0.05) the expression of colonic phenotype and CK8/18-positive cells, as evidenced by FACS analysis. Bile salt at pH 4 and bile salt followed by acid (pH 4) in succession were the strongest stimulators (Po0.01) for induction of colonic phenotype cells. Squamous (CK4 þ ) phenotype did not change by the treatments. Cox-2 expression was induced after acute treatment and increased to twofold during chronic treatment, particularly in response to acidic pH. We conclude that BAR-T cells can be utilized as an 'in vitro' model to study the effect of environmental factors and their influence on the cellular phenotype and molecular changes in the pathogenesis of esophageal cancer.

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COX2 expression, angiogenesis, proliferation and survival in Barrett's cancer

Cited by 53 publications

References 11 publications

Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt‐1/β‐Catenin Signaling Pathway

Ing4 induces Cell Growth Inhibition in Human Lung Adenocarcinoma A549 Cells by Means of Wnt‐1/β‐Catenin Signaling Pathway

Evaluation of microvascular density in Barrett's associated neoplasia

Repeated exposure to acid and bile selectively induces colonic phenotype expression in a heterogeneous Barrett's epithelial cell line

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