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. 2005 Aug 19;94(9):769–773. doi: 10.1111/j.1349-7006.2003.tb01517.x

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

Sufia Khatun 1, Jiro Fujimoto 1,✉, Hiroshi Toyoki 1, Teruhiko Tamaya 1
PMCID: PMC11160155  PMID: 12967474

Abstract

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.

References

  • 1. Folkman J. Tumor angiogenesis. Adv Cancer Res 1985; 43: 175–203. [DOI] [PubMed] [Google Scholar]
  • 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. EurJ Gynaecol Oncol 1997; 18: 349–52. [PubMed] [Google Scholar]
  • 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: 83–8. [DOI] [PubMed] [Google Scholar]
  • 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; 83: 2528–33. [DOI] [PubMed] [Google Scholar]
  • 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: 313–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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: 119–27. [PMC free article] [PubMed] [Google Scholar]
  • 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 process such as organ formation. Proc Natl Acad Sci USA 1993; 90: 7588–92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Maroulakou IG, Papas TS, Green JE. Differential expression of ets‐1 and ets‐2 proto‐oncogenes during murine embryogenesis. Oncogene 1994; 9: 1551–65. [PubMed] [Google Scholar]
  • 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: 522–31. [DOI] [PubMed] [Google Scholar]
  • 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: 647–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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: 121–32. [DOI] [PubMed] [Google Scholar]
  • 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: 109–15. [DOI] [PubMed] [Google Scholar]
  • 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: 1931–9. [PMC free article] [PubMed] [Google Scholar]
  • 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: 209–15. [PubMed] [Google Scholar]
  • 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: 61–8. [PubMed] [Google Scholar]
  • 16. Kitange G, Kishikawa M, Nakayama T, Naito S, Iseki M, Shibata S. Expression of the Ets‐1 proto‐oncogene correlates with malignant potential in human astrocytic tumors. Mod Pathol 1999; 12: 618–26. [PubMed] [Google Scholar]
  • 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: 1670–6. [DOI] [PubMed] [Google Scholar]
  • 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: 719–25. [DOI] [PubMed] [Google Scholar]
  • 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 cholangiocellular carcinoma. Oncology 2000; 58: 248–52. [DOI] [PubMed] [Google Scholar]
  • 20. 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: 6519–25. [PubMed] [Google Scholar]
  • 21. 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: 128–37. [DOI] [PubMed] [Google Scholar]
  • 22. 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: 407–16. [PubMed] [Google Scholar]
  • 23. 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: 329–34. [DOI] [PubMed] [Google Scholar]
  • 24. 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: 2292–300. [DOI] [PubMed] [Google Scholar]
  • 25. 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: 5608–14. [PubMed] [Google Scholar]
  • 26. 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: 40–5. [DOI] [PubMed] [Google Scholar]
  • 27. 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. [DOI] [PubMed] [Google Scholar]
  • 28. 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: 1598–604. [DOI] [PubMed] [Google Scholar]
  • 29. Fujimoto J, Aoki I, Toyoki H, Khatun S, Tamaya T. Clinical implications of expression of ETS‐1 related to angiogenesis in uterine endometrial cancers. Ann Oncol 2002; 13: 1605–11. [DOI] [PubMed] [Google Scholar]
  • 30. FIGO News . Int J Gynecol Obstet 1989; 28: 189–93. [Google Scholar]
  • 31. Vanden Hevvel JP, Tyson FL, Bell DA. Construction of recombinant RNA templates for use as internal standards in quantitative RT‐PCR. Biotechnology 1993; 14: 395–8. [PubMed] [Google Scholar]
  • 32. 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: 7862–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. ChoMczynski P, Sacchi N. Single‐step method of RNA isolation by acid guanidium thiocyanate‐phenol‐chloroform extraction. Anal Biochem 1987; 162: 156–9. [DOI] [PubMed] [Google Scholar]
  • 34. 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: 884–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. 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: 716–21. [PubMed] [Google Scholar]
  • 36. Bradford MA. Rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein‐dye binding. Anal Biochem 1976; 72: 315–23. [DOI] [PubMed] [Google Scholar]
  • 37. Davidson B, Reich R, Goldberg I, Gotlieb WH, Kopolovic J, Berner A, Ben‐Baruch G, Bryne M, Nesland JM. Ets‐1 messenger RNA expression is a novel marker of poor survival in ovarian carcinoma. Clin Cancer Res 2001; 7: 551–7. [PubMed] [Google Scholar]
  • 38. Nakano T, Abe M, Tanaka K, Shineha R, Satomi S, Sato T. Angiogenesis inhibition by transdominant mutant Ets‐1. J Cell Physiol 2000; 184: 255–62. [DOI] [PubMed] [Google Scholar]

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