Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Dec;89(12):1334–1342. doi: 10.1111/j.1349-7006.1998.tb00531.x

Effects of Sex Steroids and Growth Factors on Invasive Activity and 5′‐Deoxy‐5‐fluorouridine Sensitivity in Ovarian Adenocarcinoma OMC‐3 Cells

Masatsugu Ueda 1,✉, Hideji Fujii 2, Keiko Yoshizawa 2, Koji Kumagai 1, Ken Ueki 1, Yoshito Terai 1, Tomoko Yanagihara 3, Minoru Ueki 1
PMCID: PMC5921732  PMID: 10081495

Abstract

Effects of sex steroids (estradiol‐17β, E2; progesterone, Prog) and growth factors (epidermal growth factor, EGF; transforming growth factor‐α, TGF‐α) on invasive activity and 5′‐deoxy‐5‐fluorouridine (5′‐dFUrd) sensitivity of ovarian adenocarcinoma OMC‐3 cells were investigated. Tumor cell migration along a gradient of substratum‐bound fibronectin and invasion into reconstituted basement membrane were inhibited by 10 μM Prog, but stimulated by 0.1–10 nM EGF and TGF‐α in a concentration‐dependent manner. E2 did not have any effect on tumor cell migration or invasion. The zymography of tumor conditioned medium showed that the treatment of OMC‐3 cells with EGF and TGF‐α resulted in increases of type IV collagenase, stromelysin and urokinase‐type plasminogen activator (uPA). EGF and TGF‐α up‐regulated thymidine phosphorylase (dThdPase) expression of tumor cells and consequently enhanced the antiproliferative action of 5′‐dFUrd, which is converted to 5‐fluorouracil by dThdPase. E2 and Prog did not have significant effects on the expression of proteolytic enzymes and dThdPase, or on the 5′‐dFUrd sensitivity of tumor cells. The inhibitory effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor cells. These results suggest that EGF and TGF‐α simultaneously up‐regulate the potential of ovarian adenocarcinoma cells to invade extracellular matrices and their dThdPase expression, both of which are associated with the specific action of 5′‐dFUrd selectively to kill tumor cells with high invasive and metastatic potential.

Keywords: Ovarian adenocarcinoma, Invasion, Matrix metalloproteinase, Thymidine phosphorylase, 5′‐Deoxy‐5‐fluorouridine

Full Text

The Full Text of this article is available as a PDF (324.0 KB).

REFERENCES

  • 1. ) Fidler , I. J. , Gersten , D. M. and Hart , I. R.The biology of cancer invasion and metastases . Adv. Cancer Res. , 28 , 149 – 250 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Poste , G. and Fidler , I. J.The pathogenesis of cancer metastasis . Nature , 283 , 139 – 146 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Liotta , L. A. , Rao , C. V. and Barsky , S. H.Tumor invasion and the extracellular matrix . Lab. Invest. , 49 , 636 – 649 ( 1983. ). [PubMed] [Google Scholar]
  • 4. ) Woessner , J. F. J.Matrix metalloproteinases and their inhibitors in connective tissue remodeling . FASEB J. , 5 , 2145 – 2154 ( 1991. ). [PubMed] [Google Scholar]
  • 5. ) Tryggvason , K. , Hoyhtya , M. and Salo , T.Proteolytic degradation of extracellular matrix in tumor invasion . Biochim. Biophys. Acta , 907 , 191 – 217 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Matrisian , L. M.Metalloproteinases and their inhibitors in matrix remodeling . Trends Genet. , 6 , 121 – 125 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Liotta , L. A. , Steeg , P. S. and Stetler‐Stevenson , W. G.Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation . Cell , 64 , 327 – 336 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Dano , K. , Andreasen , P. A. , Grondahl‐Hansen , J. , Kristensen , P. , Nielsen , L. S. and Skriver , L.Plasminogen activators, tissue degradation and cancer . Adv. Cancer Res. , 44 , 139 – 266 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Ueda , M. , Fujii , H. , Yoshizawa , K. and Ueki , M.Biological implications of sex steroids and growth factors on the mechanism of invasion in endometrial adenocarcinoma cells . In vitro “ Biology of Sex Steroid Hormone Action ,” ed. Kuramoto H. and Gurpide E. , pp. 226 – 235 ( 1996. ). Churchill Livingstone; , Tokyo . [Google Scholar]
  • 10. ) Nakajima , M. and Chop , A. M.Tumor invasion and extracellular matrix degradative enzymes: regulation of activity by organ factors . Sem. Cancer Biol. , 2 , 115 – 127 ( 1991. ). [PubMed] [Google Scholar]
  • 11. ) Naylor , M. S. , Malik , T. A. , Stamp , G. W. H. , Jobling , T. and Balkwill , F. R.In situ detection of tumor necrosis factor in human ovarian cancer specimens . Eur. J. Cancer , 26 , 1027 – 1030 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Naylor , M. S. , Stamp , W. H. S. and Balkwill , F. R.Investigation of cytokine gene expression in human colorectal cancer . Cancer Res. , 50 , 4436 – 4440 ( 1990. ). [PubMed] [Google Scholar]
  • 13. ) Siegal , G. P. , Thorgeirsson , U. P. , Russo , R. G. , Wallace , D. M. , Liotta , L. A. and Berger , S. L.Interferon enhancement of the invasive capacity of Ewing sarcoma cells in vitro . Proc. Natl. Acad. Sci. USA , 79 , 4064 – 4068 ( 1982. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Okada , Y. , Tsuchiya , H. , Shimizu , H. , Tomita , K. , Nakanishi , I. , Sato , H. , Seiki , M. , Yamashita , K. and Hayakawa , T.Induction and stimulation of 92‐kDa gelatinase/type IV collagenase production in osteosarcoma and fibrosarcoma cell lines by tumor necrosis factor α . Biochem. Biophys. Res. Commun. , 171 , 610 – 617 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Malik , S. T. A. , Naylor , M. S. , East , N. , Oliff , A. and Balkwill , F. R.Cells secreting tumour necrosis factor show enhanced metastasis in nude mice . Eur. J. Cancer , 26 , 1031 – 1034 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Bani , M. R. , Garofalo , A. , Scanziani , E. and Giavazzi , R.Effect of interleukin‐1‐beta on metastasis formation in different tumor systems . J. Natl. Cancer Inst. , 83 , 119 – 123 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Kelly , S. A. , Gschmeissner , S. , East , N. and Balkwill , F. R.Enhancement of metastatic potential by γ‐interferon . Cancer Res. , 51 , 4020 – 4027 ( 1991. ). [PubMed] [Google Scholar]
  • 18. ) Arguello , F. , Baggs , R. B. , Graves , B. T. , Harwell , S. E. , Cohen , H. J. and Frantz , C. N.Effect of IL‐1 on experimental bone/bone‐marrow metastases . Int. J. Cancer , 52 , 802 – 807 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Niitani , H. , Kimura , K. , Saito , T. , Nakao , I. , Abe , O. , Urushizaki , I. , Ohta , K. , Yoshida , Y. , Kimura , T. , Kurihara , M. , Takeda , C. , Taguchi , T. , Terasawa , T. , Tominaga , K. , Furue , H. , Wakui , A. and Ogawa , N.Phase II study of 5′‐deoxy‐5‐fluorouridine (5′‐DFUR) on patients with malignant cancer. Multi‐institutional cooperative study . Jpn. J. Cancer Chemother. , 12 , 2044 – 2051 ( 1985. ). [PubMed] [Google Scholar]
  • 20. ) Ishitsuka , H. , Miwa , M. , Takemoto , K. , Fukuoka , K. , Itoga , A. and Maruyama , H. B.Role of uridine phosphorylase for antitumor activity of 5′‐deoxy‐5‐fluorouridine . Jpn. J. Cancer Res. , 71 , 112 – 123 ( 1980. ). [PubMed] [Google Scholar]
  • 21. ) Eda , H. , Fujimoto , K. , Watanabe , S. , Ishikawa , T. , Ohiwa , T. , Tatsuno , K. , Tanaka , Y. and Ishitsuka , H.Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5′‐deoxy‐5‐fluorouridine . Jpn. J. Cancer Res. , 84 , 341 – 347 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Eda , H. , Fujimoto , K. , Watanabe , S. , Ura , M. , Hino , A. , Tanaka , Y. , Wada , K. and Ishitsuka , H.Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′‐deoxy‐5‐fluorouridine . Cancer Chem. Pharm. , 32 , 333 – 338 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Ishikawa , T. , Ura , M. , Yamamoto , T. , Tanaka , Y. and Ishitsuka , H.Selective inhibition of spontaneous pulmonary metastasis of Lewis lung carcinoma by 5′‐deoxy‐5‐fluorouridine . Int. J. Cancer , 61 , 516 – 521 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Bulletti , C. , Jasonni , V. M. , Polli , V. , Cappuccini , F. , Galassi , A. and Flamigni , C.Basement membrane in human endometrium: possible role of proteolytic enzymes in developing hyperplasia and carcinoma . Ann. NY Acad. Sci. , 622 , 376 – 382 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Ueda , M. , Fujii , H. , Yoshizawa , K. , Abe , F. and Ueki , M.Effects of sex steroids and growth factors on migration and invasion of endometrial adenocarcinoma SNG‐M cells in vitro . Jpn. J. Cancer Res. , 87 , 524 – 533 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Yamada , T. , Ueda , M. , Otsuki , Y. , Ueki , M. and Sugimoto , O.Establishment and characterization of a cell line (OMC‐3) originating from a human mucinous cystadenocarcinoma of the ovary . Gynecol. Oncol. , 40 , 118 – 128 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) McCarthy , J. B. and Furcht , L. T.Laminin and fibronectin promote the haptotactic migration of B16 mouse melanoma cells in vitro . J. Cell Biol. , 98 , 1474 – 1480 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. ) Albini , A. , Iwamoto , Y. , Kleinman , H. K. , Martin , G. R. , Aaronson , S. A. , Kozlowski , J. M. and McEvan , R. N.A rapid in vitro assay for quantitating the invasive potential of tumor cells . Cancer Res. , 47 , 3239 – 3245 ( 1987. ). [PubMed] [Google Scholar]
  • 29. ) Heussen , C. and Dowdle , E. B.Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates . Anal. Biochem. , 102 , 196 – 202 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Nishida , M. , Hino , A. , Mori , K. , Matsumoto , T. , Yoshikubo , T. and Ishitsuka , H.Preparation of anti‐human thymidine phosphorylase monoclonal antibodies useful for detecting the enzyme levels in tumor tissues . Biol. Pharm. Bull. , 19 , 1407 – 1411 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Lowry , O. H. , Rosebrough , N. J. , Farr , A. L. and Randall , R. J.Protein measurement with the Folin phenol reagent . J. Biol. Chem. , 193 , 265 – 275 ( 1951. ). [PubMed] [Google Scholar]
  • 32. ) McGuire , W. L. , Horwitz , K. B. , Pearson , O. H. and Segaloff , A.Current status of estrogen and progesterone receptors in breast cancer . Cancer , 39 , 2934 – 2947 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Jasonni , V. M. , Bulletti , C. , Balducci , M. , Naldi , S. , Martinelli , G. , Galassi , A. and Flamigni , C.The effect of progestin on factors influencing growth and invasion of endometrial carcinoma . Ann. NY Acad. Sci. , 622 , 463 – 468 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Yoshida , K. , Tsujino , T. , Yasui , W. , Kameda , T. , Sano , T. , Nakayama , H. , Toge , T. and Tahara , E.Induction of growth factor‐receptor and metalloproteinase genes by epidermal growth factor and/or transforming growth factor‐α in human gastric carcinoma cell line MKN‐28 . Jpn. J. Cancer Res. , 81 , 793 – 798 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. ) Yudoh , K. , Matsui , H. , Kanamori , M. , Maeda , A. , Ohmori , K. and Tsuji , H.Effects of epidermal growth factor on invasiveness through the extracellular matrix in high‐ and low‐metastatic clones of RCT sarcoma in vitro . Jpn. J. Cancer Res. , 85 , 63 – 71 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES