Objective: ETS-1 has been identified as a proto-oncogene and a transcription factor for tumor angiogenesis, which is essential for the growth, invasion and metastasis of solid tumors. The aim is to investigate the clinical implications of ETS-1 expression in peritoneal metastatic lesions of ovarian cancers. Methods: In primary tumors and peritoneal metastatic lesions from 30 patients with stage III ovarian cancers, ETS-1 histoscores and ets-1 mRNA levels were determined by immunohistochemistry and competitive RT-PCR-Southern blot analysis using recombinant RNA, respectively. Results: Immunohistochemical staining revealed that ETS-1 was expressed in the cancer cells and vascular endothelial cells. ETS-1 histoscores in the endothelial cells and ets-1 mRNA levels were significantly (p < 0.05) increased in 20 of 30 peritoneal metastatic lesions of ovarian cancers. There was a significant correlation between microvessel counts (MVCs) and ETS-1 histoscores in the endothelial cells (p < 0.001) and between MVCs and ets-1 mRNA levels in the primary tumor and the peritoneal metastatic lesion of ovarian cancers (p < 0.001). Furthermore, the 24-month survival rate of patients with significantly increased ets-1 mRNA level (2/20, 10%) was significantly (p < 0.01) lower than that of patients with no change in the level (6/10, 60%) from the primary tumor to the peritoneal metastatic lesion. Conclusions: ETS-1 might be associated with peritoneal metastasis dominantly as an angiogenic mediator and additionally as an oncogene product to activate tumor invasion in ovarian cancers.

1.
Folkman J: Tumor angiogenesis. Adv Cancer Res 1985;43:175–203.
2.
Fujimoto J, Ichigo S, Hori M, Hirose R, Sakaguchi H, Tamaya T: Expression of basic fibroblast growth factor and its mRNA in advanced ovarian cancers. Eur J Gynaecol Oncol 1997;18:349–352.
3.
Fujimoto J, Ichigo S, Sakaguchi H, Hirose R, Tamaya T: Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in ovarian cancers. Cancer Lett 1998;126:83–88.
4.
Fujimoto J, Sakaguchi H, Hirose R, Ichigo S, Tamaya, T: Biologic implications of the expression of vascular endothelial growth factor subtypes in ovarian carcinoma. Cancer 1998;3:2528–2533.
5.
Fujimoto J, Sakaguchi H, Aoki I, Khatun S, Tamaya T: Clinical implications of expression of vascular endothelial growth factor in metastatic lesions of ovarian cancers. Br J Cancer 2001;85:313–316.
6.
Wernert N, Raes MB, Lassalle P, Dehouck MP, Gosselin B, Vandenbunder B, Stehelin D: c-ets proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans. Am J Pathol 1992;140:119–127.
7.
Kola I, Brookes S, Green AR, Garber R, Tymms M, Papas TS, Seth A: The Ets-1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenic processes such as organ formation. Proc Natl Acad Sci USA 1993;90:7588–7592.
8.
Maroulakou IG, Papas TS, Green JE: Differential expression of ets-1 and ets-2 proto-oncogenes during murine embryogenesis. Oncogene 1994;9:1511–1565.
9.
Iwasaka C, Tanaka K, Abe M, Sato Y: 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 1996;169:522–531.
10.
Tanaka K, Abe M, Sato Y: Roles of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in the signal transduction of basic fibroblast growth factor in endothelial cells during angiogenesis. Jpn J Cancer Res 1999;90:647–654.
11.
Oda N, Abe M, Sato Y: ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin β3. J Cell Physiol 1999;178:121–132.
12.
Sato Y, Abe M, Tanaka K, Iwasaka C, Oda N, Kanno S, Oikawa M, Nakano T, Igarashi T: Signal transduction and transcriptional regulation of angiogenesis. Adv Exp Med Biol 2000;476:109–115.
13.
Nakayama T, Ito M, Ohtsuru A, Naito S, Nakashima M, Fagin JA, Yamashita S, Sekine I: Expression of the ets-1 proto-oncogene in human gastric carcinoma: correlation with tumor invasion. Am J Pathol 1996;149:1931–1939.
14.
Ito T, Nakayama T, Ito M, Naito S, Kanematsu T, Sekine I: Expression of the ets-1 proto-oncogene in human pancreatic carcinoma. Mod Pathol 1998;11:209–215.
15.
Nakayama T, Ito M, Ohtsuru A, Naito S, Nakashima M, Sekine I: Expression of the ets-1 proto-oncogene in human thyroid tumor. Mod Pathol 1999;12:61–68.
16.
Kitange G, Kishikawa M, Nakayama T, Naito S, Iseki M, Shibata S: Expression of the Ets-1 pro-oncogene correlates with malignant potential in human astrocytic tumors. Mod Pathol 1999;12:618–626.
17.
Saeki H, Kuwano H, Kawaguchi H, Ohno S, Sugimachi K: Expression of ets-1 transcription factor is correlated with penetrating tumor progression in patients with squamous cell carcinoma of the esophagus. Cancer 2000;89:1670–1676.
18.
Ito Y, Miyoshi E, Takeda T, Sakon M, Noda K, Tsujimoto M, Monden M, Taniguchi N, Matsuura N: Expression and possible role of ets-1 in hepatocellular carcinoma. Am J Clin Pathol 2000;114:719–725.
19.
Ito Y, Miyoshi E, Takeda T, Sakon M, Tsujimoto M, Yokosaki Y, Monden M, Matsuura N: Ets-1 expression in extrahepatic bile duct carcinoma and cholangio-cellular carcinoma. Oncology 2000;58:248–252.
20.
Davidson B, Reich R, Goldberg I, et al: Ets-1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res 2001;7:551–557.
21.
Ozaki I, Mizuta T, Zhao G, Yotsumoto H, Hara T, Kajihara S, Hisatomi A, Sakai T, Yamamoto K: Involvement of the ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000;60:6519–6525.
22.
Watabe T, Yoshida K, Shindoh M, Kaya M, Fujikawa K, Sato H, Seiki M, Ishii S, Fujinaga K: The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int J Cancer 1998;77:128–137.
23.
Kitange G, Shibata S, Tokunaga Y, Yagi N, Yasunaga A, Kishikawa M, Naito S: Ets-1 transcription factor-mediated urokinase-type plasminogen activator expression and invasion in glioma cells stimulated by serum and basic fibroblast growth factors. Lab Invest 1999;79:407–416.
24.
Nakada M, Yamashita J, Okada Y, Sato H: Ets-1 positively regulates expression of urokinase-type plasminogen activator (uPA) and invasiveness of astrocytic tumors. J Neuropathol Exp Neurol 1999;58:329–334.
25.
Kitange G, Tsunoda K, Anda T, Nakamura S, Yasunaga A, Naito S, Shibata S: Immunohistochemical expression of Ets-1 transcription factor and the urokinase-type plasminogen activator is correlated with the malignant and invasive potential in meningiomas. Cancer 2000;89:2292–2300.
26.
Valter MM, Hugel A, Huang HJ, Cavenee WK, Wiestler OD, Pietsch T, Wernert N: Expression of the ets-1 transcription factor in human astrocytomas is associated with fms-like tyrosine kinase-1 (Flt-1)/ vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis. Cancer Res 1999;59:5608–5614.
27.
Pande P, Mathur M, Shukla NK, Ralhan R: Ets-1:A plausible marker of invasive potential and lymph node metastasis in human oral squamous cell carcinomas. J Pathol 1999;189:40–45.
28.
Tsutsumi S, Kuwano H, Asao T, Nagashima K, Shimura T, Mochiki E: Expression of ets-1 angiogenesis-related protein in gastric cancer. Cancer Lett 2000;160:45–50.
29.
FIGO News. Int J Gynecol Obstet 1989;28:189–193.
30.
Fujimoto J, Aoki I, Toyoki H, Khatun S, Tamaya T: Clinical implications of expression of ETS-1 related to angiogenesis in uterine cervical cancers. Ann Oncol 2002;13:1598–1604.
31.
Fujimoto J, Aoki I, Toyoki H, Khatun S, Tamaya T: Clinical implications of expression of ETS-1 related to angiogenesis in uterine cervical cancers. Ann Oncol 2002;13:1605–1611.
32.
Vanden Hevvel JP, Tyson FL, Bell DA: Construction of recombinant RNA templates for use as internal standards in quantitative RT-PCR. Biotech 1993;14:395–398.
33.
Watson DK, McWilliams MJ, Lapis P, Lautenberger JA, Schweinfest CW, Papas TS: Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc Natl Acad Sci USA 1988:85:7862–7866.
34.
Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
35.
Maeda K, Chung Y, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Onoda N, Kato Y, Sowa M: Thymidine phosphorylase/platelet-derived endothelial cell growth factor expression associated with hepatic metastasis in gastric carcinoma. Br J Cancer 1996;73:884–888.
36.
McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr: Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985;109:716–721.
37.
Nakano T, Abe M, Tanaka K, Shineha R, Satomi S, Sato T: Angiogenesis inhibition by transdominant mutant Ets-1. J Cell Physiol 2000;184:255–262.
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