Expression of Ets-1 angiogenesis-related protein in gastric cancer

doi:10.1016/S0304-3835(00)00559-0

Cancer Letters

Volume 160, Issue 1, 10 November 2000, Pages 45-50

https://doi.org/10.1016/S0304-3835(00)00559-0 Get rights and content

Abstract

The Ets-1 transcription factor plays important roles in invasiveness and angiogenesis. Using automated immunodetection, we investigated Ets-1 expression and tumor microvessel density (MVD) in relation to the clinical significance of gastric cancer. The MVD of Ets-1-positive tumors was higher than that of Ets-1-negative tumors, but the difference was insignificant. The survival rate of patients with high-MVD tumors was significantly poorer than those with low-MVD tumors, and the survival rate of patients with Ets-1-positive tumors was significantly poorer than that of those with negative ones. These results indicate that Ets-1 expression is a useful marker for predicting the outcome for patients with gastric cancer.

Introduction

Angiogenesis is essential for the growth and metastasis of solid tumors, and it depends upon the production of angiogenic factors by the host or tumor cells [1]. Among the many reported angiogenic factors, vascular endotherial growth factor (VEGF) is the most powerful endothelial-cell-specific mitogen associated with tumor neovascularization [1], [2], [3]. The c-ets-1 proto-oncogene was identified as a cellular progenitor of the v-ets oncogene, which is associated with v-myb in the genome of the avian leukemia virus, E26 [4]. The c-ets-1 gene is transiently expressed in endothelial cells during vascular development in embryos, as well as during angiogenesis in adults [5]. The protein encoded by the Ets-1 proto-oncogene is a transcription factor that regulates the expression of matrix proteases [6]. The expression of Ets-1 in endothelial cells is observed during chicken or murine embryogenesis [7], [8] and during human tumor angiogenesis [5]. The induction of Ets-1 mRNA in endothelial cells is a mutual phenomenon in response to typical angiogenic growth factors. Ets-1 appears to play an important role in angiogenesis, regulating the expression of protease and the migration of endothelial cells [9]. In the current study, patients with highly vascularized tumors had a significantly shorter survival rate than patients with poorly vascularized ones [10].

According to the TMN classification [11], pT2 gastric cancer is characterized by the tumor's invasion of the muscularis propria or subserosa, but not the serosa. Even though pT2 gastric cancer tumors can be surgically removed, the survival rate is not high, mainly because of postoperative recurrence. To determine whether Ets-1 protein expression is related to clinico-pathological features and survival rates of patients with pT2 gastric cancer, we examined the expression of Ets-1 in terms of angiogenesis-related molecules and tumor microvessel density (MVD) by an automated immunohistochemical study.

Section snippets

Patients

The study took place at the First Department of Surgery, Gunma University School of Medicine, Japan. Enrolled in the study were 102 patients with primary pT2 gastric cancer invading the muscularis propria (n=39) and the subserosa (n=63). All had undergone gastrectomy between 1993 and 1999. No distant metastasis had been detected at the time of surgery, and curative resection had been performed on all patients. The patients ranged in age from 35 to 84 years (average age: 64.0 years); 78 were

Results

Ets-1 was observed heterogeneously in carcinoma and was mainly localized in the cytoplasm and the nuclei of the tumor cells (Fig. 1). No staining was observed in the normal tissue surrounding the tumor. Ets-1 staining was defined as positive in 67.6% (69 of 102) of the gastric cancer cases.

Discussion

Persistent angiogenesis appears to play a crucial role in malignant solid tumors. In particular, distant metastasis is dependent on tumor angiogenesis [12]. Ets-1 has been implicated in both tumor invasion and neovascularization [13], and it up-regulates such proteinases as urokinase-type plasminogen activators [14] and matrix metalloproteinases [6], all of which carry Ets-responsive elements in their promoters [15]. The expression of Ets-1 in endothelial cells is observed during chicken and

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ETS transcription factors: Multifaceted players from cancer progression to tumor immunity
2023, Biochimica et Biophysica Acta - Reviews on Cancer
The E26 transformation specific (ETS) family comprises 28 transcription factors, the majority of which are involved in tumor initiation and development. Serving as a group of functionally heterogeneous gene regulators, ETS factors possess a structurally conserved DNA-binding domain. As one of the most prominent families of transcription factors that control diverse cellular functions, ETS activation is modulated by multiple intracellular signaling pathways and post-translational modifications. Disturbances in ETS activity often lead to abnormal changes in oncogenicity, including cancer cell survival, growth, proliferation, metastasis, genetic instability, cell metabolism, and tumor immunity. This review systematically addresses the basics and advances in studying ETS factors, from their tumor relevance to clinical translational utility, with a particular focus on elucidating the role of ETS family in tumor immunity, aiming to decipher the vital role and clinical potential of regulation of ETS factors in the cancer field.
Clinicopathological significance and prognostic role of microvessel density in gastric cancer: A meta-analysis
2017, Pathology Research and Practice
Citation Excerpt :
The present study is the first, to the best of our knowledge, meta-analysis of the clinicopathological significance and prognostic role of MVD in GC. In GCs, many reports have suggested that high MVD was significantly correlated with reduced survival of GC patients [3,6–30]. However, some studies have reported no significant correlation between high MVD and worse prognosis in GCs.
The aim of this study was to elucidate the clinicopathological significance and prognostic role of microvessel density (MVD) in gastric cancer (GC) through a meta-analysis.
This meta-analysis included 4094 patients from 26 eligible studies. We investigated the correlation between MVD and clinicopathological characteristics, including survival rate. In addition, subgroup analysis based on microscopic magnification among evaluation criteria of MVD was performed.
High MVD was significantly correlated with worse overall and disease-free survival rates [hazard ratio (HR), 3.028, 95% confidence interval (CI) 2.105–4.357 and HR 2.045, 95% CI 1.530–2.732, respectively]. MVD was significantly increased in GC with diffuse type of Lauren’s classification [mean difference (MD) 3.091, 95% CI 0.615–5.567], lymphatic invasion (MD 8.262, 95% CI 3.310–13.214), lymph node metastasis (MD 5.730, 95% CI 2.444–9.016), higher pT stage (pT3-4) (MD 7.093, 95% CI 0.060–14.126) and higher pTNM stage (III–IV) (MD 3.023, 95% CI 0.181–5.865). However, MD of MVD was not significantly different in regard to vascular invasion (MD 7.430, 95% CI 1.015–15.875), tumor differentiation (MD 5.501, 95% CI 1.353–12.355) and tumor size (MD 4.731, 95% CI 2.003–11.465).
Taken together, higher MVD was significantly correlated with worse prognosis. In addition, MVD was significantly higher in GC with aggressive tumor behavior than in GC without aggressive features.
The role of the transcription factor Ets1 in carcinoma
2015, Seminars in Cancer Biology
Citation Excerpt :
In addition, increased Ets1 protein levels were found to correlate with higher levels of the invasion-promoting factors uPA (urokinase-type plasminogen activator) in breast and lung cancer [59,195] and with higher expression of the matrix metalloproteinase stromelysin-3 in oral cancer [197]. High Ets1 expression in cancer cells was also associated to lymph node and/or distant metastasis, as shown for colorectal, gastric, lung, oral and ovarian cancer [189,190,193,195,197–201]. Moreover, Ets1 expression was linked to higher microvessel density in cervical, colorectal, endometrial, oral and ovarian cancer and was shown to correlate with the angiogenesis-stimulating factors VEGF (vascular endothelial growth factor), bFGF (basic fibroblast growth factor) and Ang2 (angiopoietin-2) [197,202–207].
Ets1 belongs to the large family of the ETS domain family of transcription factors and is involved in cancer progression. In most carcinomas, Ets1 expression is linked to poor survival. In breast cancer, Ets1 is primarily expressed in the triple-negative subtype, which is associated with unfavorable prognosis. Ets1 contributes to the acquisition of cancer cell invasiveness, to EMT (epithelial-to-mesenchymal transition), to the development of drug resistance and neo-angiogenesis. The aim of this review is to summarize the current knowledge on the functions of Ets1 in carcinoma progression and on the mechanisms that regulate Ets1 activity in cancer.
Study of the topographic distribution of ets-1 protein expression in invasive breast carcinomas in relation to tumor phenotype
2006, Cancer Detection and Prevention
Background: Ets-1 is a transcription factor, implicated in the regulation of expression of various genes’. The aim of the present study was to investigate the expression of ets-1 protein in invasive breast carcinomas and its correlation with classic clinicopathological parameters, patients’ survival and various biological markers. Methods: Immunohistochemistry was performed in paraffin-embedded tissue specimens from 149 invasive breast carcinomas to detect the proteins ets-1, p53, topoisomerase IIα, matrix metalloproteinase-7 (MMP-7) and urokinase-type plasminogen activator receptor (uPAR). Results were subjected to univariate and multivariate statistic analysis. Results: Ets-1 protein was detected in the 77.9% of the cases in the cytoplasm, in the 46.3% in the nucleus of the malignant cells, and in stromal fibroblasts as well. Cytoplasmic ets-1 was inversely correlated with nuclear and histologic grade of the tumor (p = 0.004 and 0.033, respectively) and topoisomerase IΙα (p = 0.057), while nuclear ets-1 showed a positive association with p53 (p = 0.002). Stromal ets-1 revealed a negative correlation with estrogen receptors (ER) (p = 0.003) and a positive one with stromal uPAR and MMP-7 as well (p = 0.048 and 0.066, respectively). The univariate statistic analysis showed nuclear ets-1 to be related to a shortened overall survival of the postmenopausal patients (p = 0.032). Conclusions: Ets-1 seems to be related to a different tumor phenotype according to its topographic distribution, with nuclear localization being associated with decreased apoptotic potential of the malignant cells through its relation to the mutant p53 protein, cytoplasmic being related to a favorable tumor phenotype and stromal ets-1 being related to tumor invasion.
20 Role of Immunohistochemical Expression of ETS-1 Factor in Ovarian Carcinoma
2006, Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas
Clinical implications of expression of ETS-1 related to angiogenesis in uterine endometrial cancers
2002, Annals of Oncology
Angiogenesis is essential for development, growth and advancement of solid tumors. During angiogenesis, ETS-1 is strongly expressed in vascular endothelial cells and the adjacent interstitial cells, while the inhibition of ETS-1 expression leads to suppression of angiogenesis. This prompted us to study the clinical implications of ETS-1 in relation to angiogenesis in uterine endometrial cancers.
Sixty patients underwent resection for uterine endometrial cancers. From the tissues of 60 uterine endometrial cancers, the levels of ets-1 mRNA, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor(PD-ECGF) and interleukin (IL)-8 were determined by competitive RT–PCR using recombinant RNA and enzyme immunoassay, and the localization and counts of microvessel were determined by immunohistochemistry.
There was a significant correlation between microvessel count and ets-1 gene expression levels in uterine endometrial cancers. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. The level of ets-1 mRNA tended to increase with increasing disease stage. Furthermore, the level of ets-1 mRNA correlated with levels of VEGF in well-differentiated adenocarcinomas (G1) and of bFGF in moderately differentiated adenocarcinomas (G2) and poorly differentiated adenocarcinomas (G3).
ETS-1 is a possible angiogenic mediator in uterine endometrial cancers.

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View full text

Expression of Ets-1 angiogenesis-related protein in gastric cancer

Abstract

Introduction

Section snippets

Patients

Results

Discussion

J. Biol. Chem.

Biochem. Biophys. Acta

J. Biol. Chem.

Vascular endothelial growth factor expression and angiogenesis in non-small-cell lung carcinoma

Int. J. Oncol.

Expression of vascular endotherial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer

Cancer Res.

A putative second cell-derived oncogene of avian leukemia retrovirus E26

Nature

C-ets1 protooncogene is a transcription factor expressed in endotherial cells during tumor vascularization and other forms of angiogenesis in humans

Am. J. Pathol.

The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins

EMBO J.

The Ets 1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation

Proc. Natl. Acad. Sci. USA

Differential expression of ets-1 and ets-2 proto-oncogenes during murine embryogenesis

Oncogene

Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells

J. Cell Physiol.

Tumor angiogenesis and metastasis-correlation in invasive breast carcinoma

N. Engl. J. Med.