Expression of Ets-1 transcription factor is correlated with penetrating tumor progression in patients with squamous cell carcinoma of the esophagus

Saeki, Hiroshi; Kuwano, Hiroyuki; Kawaguchi, Hidetoshi; Ohno, Shinji; Sugimachi, Keizō

doi:10.1002/1097-0142(20001015)89:8<1670::aid-cncr4>3.0.co;2-j

Cited by 44 publications

(38 citation statements)

References 19 publications

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“…[13][14][15][16][17][18][19] In the present study, ets-1 mRNA levels correlated with microvessel density observed in the immunohistochemical staining for factor VIII-related antigen. Furthermore, VEGF levels correlated with ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels in the cancer tissues of all cases.…”

Section: Discussionmentioning

confidence: 55%

“…11,12) Ets-1 is expressed in various gastric, pancreatic, esophageal, and hepatocellular and cholangiocellular carcinomas and in thyroid and astrocytic tumors, and acts as a proto-oncogene. [13][14][15][16][17][18][19] ETS-1 is up-regulated and involved in the overexpression of MMP-7 in hepatocellular carcinoma cells, 20) and positively regulates the expression of u-PA in breast cancer, glioma, astrocytoma and meningioma cells, being associated with invasive potential and phenotypes. [21][22][23][24] ETS-1 expression is induced by bFGF in glioma cells, in which it is related to invasive potential, 22) and by VEGF in astrocytomas, in which it is related to angiogenesis.…”

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confidence: 99%

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Clinical implications of expression of ETS‐1 in relation to angiogenesis in ovarian cancers

Khatun¹,

Fujimoto²,

Toyoki³

et al. 2003

Cancer Science

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ETS-1 has been identified as a transcription factor involved in tumor angiogenesis, which is essential for the growth, invasion, and metastasis of solid tumors. This result prompted us to study whether ETS-1 works as an angiogenic mediator in ovarian cancers. Immunohistochemical staining revealed that ETS-1 was expressed in vascular endothelial cells and in cancer cells of ovarian cancers. There was a significant correlation between microvessel counts and both ETS-1 histoscores and ets-1 mRNA levels in ovarian cancers. Both ETS-1 histoscores and ets-1 mRNA levels increased with the progression of ovarian cancers. Furthermore, the 24-month survival rate of 30 patients with high ets-1 (high ETS-1 histoscores and high ets-1 mRNA levels) was 30%, while that of 30 other patients with low ets-1 (low ETS-1 histoscores and ets-1 mRNA levels) was 70%. There was a significant difference between the 24-month survival rates of the 30 patients with high ets-1 and the 30 with low ets-1. This indicates that ETS-1 might act as an angiogenic mediator in, and be a prognostic factor for, ovarian cancers. ngiogenesis is essential for development, growth and progression of solid tumors.1) The angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF; identical with thymidine phosphorylase (TP)), and interleukin (IL)-8 modulate angiogenesis in ovarian cancers.2-5) bFGF was found to be expressed in both cancer and interstitial cells of ovarian cancers, and its levels correlated with clinical stage, but not obviously with the patients' prognosis.2) PD-ECGF was dominantly expressed in interstitial cells of ovarian cancers, and a high level correlated with poor prognosis.3) VEGF, particularly VEGF 165 isomer, was dominantly expressed in cancer cells of primary ovarian cancers, and its level correlated with the patients' prognosis, regardless of histopathological findings.4) Furthermore, patients with higher VEGF levels in peritoneal metastatic lesions than in the primary tumors had poorer prognosis. 5)During angiogenesis, ETS-1 is strongly expressed in vascular endothelial cells and in the adjacent interstitial cells. 6) Once angiogenesis has ended, ETS-1 expression is down-regulated. 7,8) The representative angiogenic factors VEGF and bFGF immediately induce ETS-1 expression in the early stage of angiogenesis, while the inhibition of ETS-1 expression leads to suppression of angiogenesis.9, 10) The proteases urokinase typeplasminogen activator (u-PA), matrix metalloprotease (MMP)-1, MMP-3 and MMP-9 have a conserved ETS-binding motif, and transcription factor ETS-1 converts vascular endothelial cells to angiogenic phenotypes by inducing expression of u-PA, 12) Ets-1 is expressed in various gastric, pancreatic, esophageal, and hepatocellular and cholangiocellular carcinomas and in thyroid and astrocytic tumors, and acts as a proto-oncogene. [13][14][15][16][17][18][19] ETS-1 is up-regulated and involved in the overexpression of MMP-7 in hepa...

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Section: Discussionmentioning

confidence: 55%

mentioning

confidence: 99%

Clinical implications of expression of ETS‐1 in relation to angiogenesis in ovarian cancers

Khatun¹,

Fujimoto²,

Toyoki³

et al. 2003

Cancer Science

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“…The Ets1 transcription factor is normally expressed within the proliferative basal layer of the epidermis (Nagarajan et al, 2009), but in many squamous cell cancers, Ets1 is overexpressed in malignant keratinocytes, where its expression is correlated with invasion and metastasis (Bai et al, 2009;Endo et al, 2006;Keehn et al, 2004;Pande et al, 1999;Saeki et al, 2000;Vairaktaris et al, 2007). In order to address the potential role of Ets1 in keratinocyte biology and in the induction of squamous cell tumors, we generated a mouse model in which we can inducibly express Ets1 in keratinocytes that have already begun their differentiation process.…”

Section: Discussionmentioning

confidence: 99%

“…In normal tissues, Ets1 is expressed only in the basal layer of stratified squamous epithelium (Nagarajan et al, 2009). However, in a large fraction of SCC tumors, Ets1 is highly expressed within the malignant keratinocytes, and its levels directly correlate with the invasive and metastatic potential of the tumor (Bai et al, 2009;Endo et al, 2006;Keehn et al, 2004;Pande et al, 1999;Saeki et al, 2000;Vairaktaris et al, 2007). Tumors that express high levels of Ets1 typically also express high levels of several matrix metalloprotease (Mmp) genes (Dittmer, 2003;Hahne et al, 2008;Lincoln and Bove, 2005) and Ets1 has been shown to directly regulate expression of multiple Mmp genes (Baillat et al, 2006;Nagarajan et al, 2009;Ozaki et al, 2000;Reisdorff et al, 2002;Wei et al, 2009;Westermarck et al, 1997).…”

Section: Ets1 Blocks Terminal Differentiation Of Keratinocytes and Inmentioning

confidence: 99%

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

Nagarajan

Chin

Wang

et al. 2010

Journal of Cell Science

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SummaryThe transcription factor Ets1 is normally expressed in the proliferative layer of stratified epithelium, but expression of Ets1 is significantly upregulated in squamous cell carcinomas. How elevated levels of Ets1 impact tumor initiation and progression is not well understood. To determine the biological consequences of overexpression of Ets1, we developed a transgenic mouse model that allows induction of Ets1 expression in keratinocytes of stratified epithelium in a regulatable fashion. Induction of Ets1 during embryonic development results in a dramatic alteration in epidermal structure and function by suppressing the expression of multiple stratum corneum constituents, while at the same time inducing expression of EGF ligands, AP1 transcription factors and matrix metalloproteases. Interestingly, expression of certain immune-related genes, including defensins, chemokines and cytokines was increased as well, suggesting a possible role for immune dysregulation in the promotion of squamous dysplasia. Experiments using cultured mouse keratinocytes indicate that Ets1 can induce expression of some of these mediators in a cell-intrinsic fashion. Collectively, our data reveal that elevated expression of Ets1 has a much broader array of pro-tumorigenic effects on epithelial cells than previously appreciated.

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“…The expression of Ets-1 has been identified in various neoplasms including lung carcinoma (Bolon et al 1995), stomach (Nakayama et al 1996;Yu et al 2003), pancreas (Ito et al 1998), liver (Ozaki et al 2000), esophagus (Saeki et al 2000), ovary (Davidson et al 2001), breast (Buggy et al 2004;Katayama et al 2005), tongue (Endo et al 2006), and prostate (Alipov et al 2005). In these studies, it was speculated that Ets-1 might be involved not only in tumor invasion but also in remodeling of connective tissue.…”

Section: Discussionmentioning

confidence: 99%

Ets-1 Proto-Oncogene as a Potential Predictor for Poor Prognosis of Lung Adenocarcinoma

Yamaguchi

Nakayama

Nanashima

et al. 2007

Tohoku J. Exp. Med.

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The protooncogene Ets-1 is a transcription factor that is known to regulate certain matrix metalloproteinases and plasminogen activator, which have been associated with malignant behaviors in solid carcinomas. We hypothesized that Ets-1 expression is also associated with tumor progression and a worse prognosis in lung carcinoma patients. To clarify the role of the Ets-1 proto-oncogene, the expression of Ets-1 in non-small cell lung carcinomas using 156 paraffin-embedded specimens was determined in surgically resected tissue samples. Immunohistochemical staining showed Ets-1 expression in 82 cases of 156 carcinomas (53%): 36 of 52 (69%) squamous cell carcinomas, 41 of 96 (43%) adenocarcinomas, and 5 of 8 (63%) other carcinomas. In adenocarcinomas, a higher proportion of acinar type expressed Ets-1 compared to papillary or alveolar type ( p < 0.05). The proportion of adenocarcinoma that expressed Ets-1 increased with poorer histologic differentiation of the adenocarcinoma ( p < 0.05). Ets-1 positive adenocarcinomas had a larger mean size than Ets-1 negative adenocarcinomas ( p < 0.01). In adenocarcinoma patients, expression of Ets-1 was associated with disease-free ( p = 0.09) and overall survivals ( p < 0.05) after lung resection. Such relationship was not observed among squamous cell carcinoma patients. Our findings indicate that Ets-1 expression is related to histopathological differentiation, morphogenesis, and tumor progression of lung adenocarcinomas. Ets-1 appears to be a useful predictor of poor prognosis after surgical resection in lung adenocarcinoma patients. Ets-1 expression could be used to evaluate the malignant behaviors of lung adenocarcinomas.Ets-1; non-small cell lung cancer; histologic differentiation; subtype; prognosis

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Expression of Ets-1 transcription factor is correlated with penetrating tumor progression in patients with squamous cell carcinoma of the esophagus

Cited by 44 publications

References 19 publications

Clinical implications of expression of ETS‐1 in relation to angiogenesis in ovarian cancers

Clinical implications of expression of ETS‐1 in relation to angiogenesis in ovarian cancers

Ets1 blocks terminal differentiation of keratinocytes and induces expression of matrix metalloproteases and innate immune mediators

Ets-1 Proto-Oncogene as a Potential Predictor for Poor Prognosis of Lung Adenocarcinoma

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