Signal Transduction and Transcriptional Regulation of Angiogenesis

Sato, Yasufumi; Abé, Mayumi; Tanaka, Katsuhiro; Iwasaka, Chika; Oda, Noriichi; Kanno, Satoshi; Oikawa, Manami; Nakano, Tohru; Igarashi, Tadashi

doi:10.1007/978-1-4615-4221-6_9

Cited by 51 publications

(36 citation statements)

References 25 publications

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“…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 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.…”

Section: )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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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: )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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“…In model systems, increased expression of Ets-1 was found to be associated with enhanced angiogenesis and the invasive phenotype (Vandenbunder et al, 1994a, b;Ito et al, 1998;Sato et al, 2000). In addition, several angiogenic factors, such as the vascular endothelial growth factor (VEGF) and both acidic and basic fibroblast growth factor (FGF), have been shown to induce expression of Ets-1 (Wernert et al, 1994;Sato et al, 2000).…”

mentioning

confidence: 99%

“…In addition, several angiogenic factors, such as the vascular endothelial growth factor (VEGF) and both acidic and basic fibroblast growth factor (FGF), have been shown to induce expression of Ets-1 (Wernert et al, 1994;Sato et al, 2000). In a preliminary report, Span et al (2002) recently showed that high expression of Ets-1 was associated with adverse prognosis in breast cancer.…”

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confidence: 99%

Overexpression of the Ets-1 transcription factor in human breast cancer

et al. 2004

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The Ets family of transcription factors regulate expression of multiple genes involved in tumour progression. The aim of this study was to investigate the expression of Ets-1 in a large panel of human breast cancers and relate its levels to the parameters of tumour progression and metastasis. Using RT -PCR, Ets-1 mRNA was detected in 30 out of 42 (71%) fibroadenomas and 131 out of 179 (73%) primary breast carcinomas. Similarly, levels of Ets-1 mRNA were not significantly different in fibroadenomas and primary breast carcinomas. Using Western blotting, four forms of the Ets-1 protein were detected, that is, p33, p42, p51 and p52. Levels of both p51 and p52 but not p33 and p42 were present at significantly higher levels in the carcinomas compared to the fibroadenomas (for p51, Po0.007; for p52, Po0.02; Mann -Whitney U-test). Levels of p52, p51 and p33 correlated significantly with uPA protein levels (Po0.01), while only levels of p52 correlated significantly with HER-2/neu protein levels (Po0.01). Using immunohistochemistry, Ets-1 was found predominantly in tumour cells, but was also detected in some stromal cells surrounding tumour islands. We conclude that, while at the mRNA level, Ets-1 was found at similar levels in fibroadenomas and primary breast carcinomas, higher protein levels were detected in the cancers compared to the benign specimens. Since p52, p51 and p33 correlate with uPA levels, these forms of Ets-1 may play a role in breast cancer metastasis.

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“…Therefore, the antiangiogenic effect of fumagillin could be a consequence of the downregulation of both Ets-1 expression and Ets-1 activation by phosphorylation through the Erk-1/-2 signaling pathway (Figure 8). Indeed, this dual effect of fumagillin on Ets-1 is able to totally abrogate Stromelysin-1 induction, an MMP also involved in angiogenesis (Sato et al, 2000). It is noteworthy that PPI-2458, a member of the fumagillin class of compounds, potently inhibits the proliferation of human fibroblast-like synoviocytes derived from rheumatoid arthritis patients and displays a significant in vivo activity in a rat model of rheumatoid arthritis.…”

Section: Stromelysin-1 Promoter Regulation By Endogenous Ets-1 D Bailmentioning

confidence: 97%

“…There is a strong presumption that transcriptional misregulation of Stromelysin-1 could be mediated by Ets-1. Indeed, on the one hand, the same proinflammatory cytokines as IL-1b and tumor necrosis factor (TNFa) are able to activate both Stromelysin-1 and Ets-1 (Mauviel, 1993;Redlich et al, 2001), and on the other hand, patterns of increased coexpression of both genes have been documented in processes such as rheumatoid arthritis (Sun and Yokota, 2001), glomerulonephritis (Naito et al, 2000), angiogenesis (Sato et al, 2000) and tumor invasion (Wernert et al, 1994). It is all the more important that Ets-1, among all the other Ets proteins, is considered as an independent marker of poor prognosis in various cancer types (Span et al, 2002;Mukherjee et al, 2003;Tokuhara et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter

et al. 2006

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Regulation of the gene expression of Stromelysin-1 (matrix metalloproteinase-3), a member of the matrix metalloproteinase family, is critical for tissue homeostasis. The Stromelysin-1 promoter is known to be transactivated by Ets proteins through palindromic headto-head Ets binding sites (EBS), an unusual configuration among metalloproteinase promoters. Patterns of increased co-expression of Stromelysin-1 and Ets-1 genes have been observed in pathological processes such as rheumatoid arthritis, glomerulonephritis and tumor invasion. In this context, we show in a synovial fibroblastic model cell line (HIG-82), which is able to co-express Stromelysin-1 and Ets-1, that the EBS palindrome is essential for the expression of Stromelysin-1. More precisely, using electrophoretic mobility shift assays, DNA affinity purification and chromatin immunoprecipitation, we demonstrate that endogenous Ets-1, but not Ets-2, is present on this palindrome. The use of a dominant-negative form of Ets-1 and the decrease of Ets-1 amount either by fumagillin, an antiangiogenic compound, or by short interfering RNA show that the activation rate of the promoter and the expression of Stromelysin-1 correlate with the level of endogenous Ets-1. Thus, it is the first demonstration, using this cellular model, that endogenously expressed Ets-1 is actually a main activator of the Stromelysin-1 promoter through its effective binding to the EBS palindrome.

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Signal Transduction and Transcriptional Regulation of Angiogenesis

Cited by 51 publications

References 25 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

Overexpression of the Ets-1 transcription factor in human breast cancer

Stromelysin-1 expression is activated in vivo by Ets-1 through palindromic head-to-head Ets binding sites present in the promoter

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