Immunohistochemical expression of Ets-1 transcription factor and the urokinase-type plasminogen activator is correlated with the malignant and invasive potential in meningiomas

Kitange, Gaspar J.; Tsunoda, Keishi; Anda, Takeo; Nakamura, Shunsuke; Yasunaga, Akio; Naito, Shinji; Shibata, Shôbu

doi:10.1002/1097-0142(20001201)89:11<2292::aid-cncr18>3.0.co;2-0

Cited by 37 publications

(24 citation statements)

References 22 publications

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“…Previously, another member of the Ets family, that is, PEA3, was also found to correlate with HER-2/neu in breast cancer (Shepherd et al, 2001) and EBSs have been found in the HER-2/neu promoter (Chiang et al, 2000). Our finding of a correlation between Ets-1 protein levels and both HER-2/neu and uPA is consistent with previous data showing a role for Ets-1 in invasive processes (Vandenbunder et al, 1994a;Wernert et al, 1994;Nakada et al, 1999;Pande et al, 1999;Kitange et al, 2000;Naito et al, 2000).…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

et al. 2004

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“…[15][16][17] Ets-1 expression is not restricted to the tumor cells since its mRNA is also found in the stromal fibroblasts of invasive tumors. 18,19 Ets-1 is not expressed in quiescent endothelial cells in adult tissues, but it is induced by proliferating and migrating endothelial cells but not after these cells have reached confluence.…”

Section: Discussionmentioning

confidence: 99%

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

et al. 2004

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Ets-1 transcription factor has been associated with tumor progression in various carcinomas, but its expression in malignant melanoma was only recently described. The study was conducted in two steps: exploratory and confirmatory. In the first step, we studied 69 primary melanomas, 28 metastatic melanomas, 10 usual intradermal nevi and 13 various melanocytic skin lesions. In the second step, an additional group of 98 patients with follow-up of up to 200 months was also evaluated. Immunohistochemical analysis of formalinfixed/paraffin-embedded tissues was performed using 1G11 antibody and polymer conjugate for visualization. While Ets-1 was variably expressed in 83% primary melanomas in exploratory and 69% in the confirmatory group, the expression of Ets-1 was also found in normal benign melanocytes and all nevi. Analysis of the exploratory group revealed lower expression of Ets-1 in primary melanomas than in common nevi (P ¼ 0.048, Mann-Whitney U-test) and metastatic melanomas expressed significantly less Ets-1 than primary melanomas (P ¼ 0.015, Mann-Whitney U-test). There was a negative correlation between Ets-1 expression and the largest dimension of the primary tumors (r ¼ 0.23, P ¼ 0.034, Spearman's correlation rank test), but no correlation with the depth of tumor invasion (Breslow thickness) or the presence of ulceration was found. Analyses of the confirmatory group revealed no association between Ets-1 expression with disease-specific survival or time to treatment failure. However, a statistical trend was found for worse outcome for those primary melanomas that had strong expression (H-score 4100) of Ets-1 (P ¼ 0.054). Ets-1 is expressed in benign melanocytes probably due to their neural crest origin. We conclude that Ets-1 expression cannot be used to differentiate between benign and malignant melanocytic lesions and it has no definite association with clinical outcome. At the same time, its role in tumor progression in some cases of malignant melanoma cannot be entirely excluded. Keywords: Ets-1; malignant melanoma; survival; neural crest Malignant melanoma originates from melanocytes derived from the neural crest. 1 It is the most deadly form of skin cancer, whose incidence is rapidly increasing worldwide. 2 To date the most reliable prognostic marker of malignant melanoma is the vertical thickness (Breslow thickness) of the primary tumor. 3,4 Although progression of malignant melanoma occurs through a series of well-defined steps, the knowledge of genetic and phenotypic background for the disease is still rather scarce. The proto-oncogene ETS-1 belongs to the ETS family of transcription factors that also include, among others, ets-2, elf-1, fli-1 and PU-1. 5-7 Ets-1 plays an important role in cancer progression due to its ability to activate transcription of metastasis-, angiogenesis-and invasion-associated genes. [8][9][10][11][12] In a limited study on 10 melanomas and 24 benign melanocytic lesions, Keehn et al 13 recently reported expression of the Ets-1 in melanocytic lesions and suggested that E...

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“…[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.…”

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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Immunohistochemical expression of Ets-1 transcription factor and the urokinase-type plasminogen activator is correlated with the malignant and invasive potential in meningiomas

Cited by 37 publications

References 22 publications

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

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

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

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

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