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Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: Diminution of tumorigenicity with a corresponding decrease in the production of prostaglandin E2


We have previously reported that both regressor (QR) and progressor (metastatic, QP) clones were obtained after the in vitro exposure of a mouse fibrosarcoma BMT-11 cl-9 to quercetin [17]. In this study, we investigated possible mechanisms of spontaneous regression of QR clones as compared with tumorigenic QP and BMT-11 cl-9 tumor clones. We observed that BMT-11 cl-9 cells produced relatively high amounts of prostaglandin E2 (PGE2) during in vitro culture. The average production by 11 subclones of BMT-11 cl-9 cells was 9236±2829 pg/ml whereas that by 9 QR clones was 3411±2213 pg/ml (P <0.02). Indomethacin not only inhibited in vitro PGE2 synthesis by QP clones (high-PGE2 producers) but also the s.c. growth of QP clones in mice. Chronological changes in host immune responses to tumor-associated antigen were measured by cytotoxic T lymphocyte (CTL) activity examined after mixed lymphocyte/tumor cell culture of spleen cells obtained from tumor-bearing mice. The CTL activity disappeared abruptly in the spleen of QP-clonebearing mice 21 days after the inoculation of tumors, whereas the spleen cells of QR-clone-inoculated mice retained their CTL activity. We determined that the mechanism responsible for the regression of these regressor clones is not due to any qualitative or quantitative increase in pre-existing membrane antigens, nor the emergence of new antigen(s) on the cell surface of the QR clones; nor was it due to enhanced susceptibility of QR clones to natural killer cells, lymphokine-activated killer cells and macrophages. These finding suggest that the regression mechanism of QR clones may be the diminished inhibition of host response to tumor-associated antigen caused by the reduced production of PGE2 by QR clones.

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  1. 1.

    Balch CM, Dougherty PA, Cloud GA, Tilden AB (1984) Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. Surgery 95: 71

  2. 2.

    Bennett A, Del Tacca M, Stamford IF, Zebro T (1977) Prostaglandins from tumors of human large bowel. Br J Cancer 35: 881

  3. 3.

    Bennett A, Charlier EM, McDonald AM, Simpson JS, Stamford IF (1977) Prostaglandins and breast cancer. Lancet ii: 624

  4. 4.

    Bonmassar E, Bonmassar A, Vadlamudi S, Goldin A (1970) Immunological alteration of leukemic cells in vivo after treatment with an antitumor drug. Proc Natl Acad Sci USA 66: 1089

  5. 5.

    Boon T, Kellermann O (1977) Rejection by syngeneic mice of cell variants obtained by mutagenesis of malignant teratocarcinoma cell line. Proc Natl Acad Sci USA 74: 272

  6. 6.

    Boon T, Van Snick J, Van Pel A, Uyttenhove C, Marchard M (1980) Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. II. T-lymphocyte-mediated cytolysis. J Exp Med 152: 1184

  7. 7.

    Carlow D, Kerbel R, Feltis T, Elliott B (1985) Enhanced expression of Class I major histocompatibility complex gene (Dk) products on immunogenic variants of a spontaneous murine carcinoma. J Natl Cancer Inst 75: 291

  8. 8.

    Elliott BE, Carlow DA, Ivimey L, Arnold M, Hampton N, Bosman P (1987) In situ augmentation of Class I major histocompatibility antigen expression on immunogenic variants of a spontaneous murine mammary carcinoma. Cancer Res 47: 4915

  9. 9.

    Frost P, Kerbel R, Bauer E, Tartamella-Biondo R, Cefalu W (1983) Mutagen treatment as a means for selecting immunogenic variants from otherwise poorly immunogenic malignant murine tumors. Cancer Res 43: 125

  10. 10.

    Frost P, Liteplo RG, Donaghue T, Kerbel RS (1984) Selection of strongly immunogenic “tum-” variants from tumors at high frequency using 5-azacytidine. J Exp Med 159: 1491

  11. 11.

    Fulton A, Roi L, Howard L, Russo J, Brooks S, Brennan MJ (1982) Tumor-associated prostaglandins in patients with primary breast cancer: relationship to clinical parameters. Breast Cancer Res Treat 2: 331

  12. 12.

    Gorelik E, Peppoloni S, Overton R, Herberman RB (1985) Increase in H-2 antigen expression and immunogenicity of BL6 melanoma cells treated with N-Methyl-N′-nitronitrosoguanidine. Cancer Res 45: 5341

  13. 13.

    Goronzy J, Weyand CM, Fathman CG (1986) Long-term humoral unresponsiveness in vivo, induced by treatment with monoclonal antibody against L3T4. J Exp Med 164: 911

  14. 14.

    Herrman K (1976) Flavonols and flavones in food plants: a review. J Food Technol 11: 433

  15. 15.

    Hosokawa M, Okayasu T, Ikeda K, Katoh H, Suzuki Y, Kobayashi H (1983) Alteration of immunogenicity of xenogenized tumor cells in syngeneic rats by the immune response to virus-associated antigens produced on immunizing cells. Cancer Res 43: 2301

  16. 16.

    Ishikawa M, Hosokawa M, Oh-hara N, Niho Y, Kobayashi H (1987) Marked granulocytosis in C57BL/6 mice bearing a transplanted BMT-11 fibrosarcoma. J Natl Cancer Inst 78: 567

  17. 17.

    Ishikawa M, Okada F, Hamada J-I, Hosokawa M, Kobayashi H (1987) Changes in the tumorigenic and metastatic properties of tumor cells treated with quercetin or 5-azacytidine. Int J Cancer 39: 338

  18. 18.

    Jaffe BM (1974) Prostaglandins and cancer: an Update. Prostaglandins 6: 453

  19. 19.

    Kerbel RS, Frost P, Liteplo R, Carlow DA, Elliott BE (1984) Possible epigenetic mechanisms of tumor progression: induction of highfrequency heritable but phenotypically unstable changes in the tumorigenic and metastatic properties of tumor cell populations by 5-azacytidine treatment. J Cell Physiol Suppl 3: 87

  20. 20.

    Kobayashi H (1979) Viral xenogenization of intact tumor cells. Adv Cancer Res 30: 279

  21. 21.

    Kobayashi H (1986) The biological modification of tumor cells as a means of inducing their regression: an overview. J Biol Resp Modifiers 5: 1

  22. 22.

    Kobayashi H, Sendo F, Shirai T, Kaji H, Kodama T, Saito H (1969) Modification in growth of transplantable rat tumors exposed to Friend virus. J Natl Cancer Inst 32: 413

  23. 23.

    Kobayashi H, Sendo F, Kaji H, Shirai T, Saito H, Takeichi N, Hosokawa M, Kodama T (1970) Inhibition of transplantable rat tumors by immunization with identical tumor cells infected with Friend virus. J Natl Cancer Inst 44: 11

  24. 24.

    Kobayashi H, Kodama T, Gotohda E (1977) Xenogenization of tumor cells. Hokkaido Univ Med Libr Ser 9: 1

  25. 25.

    Kripke ML (1981) Immunologic mechanism in UV radiation carcinogenesis. Adv Cancer Res 34: 69

  26. 26.

    Kuzumaki N, Fenyo EM, Giovanella B, Klein G (1978) Increased immunogenicity of low-antigenic rat tumors after superinfection with endogenous murine C-type virus in nude mice. Int J Cancer 21: 62

  27. 27.

    Lanni L, Becker EL (1985) Inhibition of neutrophil phospholipase A2 by p-bromophenylacyl bromide, nordihydroguaiaretic acid, 5, 8, 11, 14-eicosatetrayenoic acid and quercetin. Int Archs Allergy appl Immun 76: 214

  28. 28.

    Lee TP, Matteliano ML, Middleton E Jr (1982) Effect of quercetin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Science 31: 2765

  29. 29.

    MacGregor JT (1986) Mutagenic and carcinogenic effects of flavonoids. Prog Clin Biol Res 213: 411

  30. 30.

    Nakayasu M, Sakamoto H, Terada M, Nagao M, Sugimura T (1986) Mutagenicity of quercetin in chinese hamster lung cells in culture. Mutat Res 174: 79

  31. 31.

    Pelus LM, Bockman RS (1979) Increased prostaglandin synthesis by macrophages from tumor-bearing mice. J Immunol 123: 2118

  32. 32.

    Peppoloni S, Herberman RB, Gorelik E (1985) Induction of highly immunogenic variants of Lewis lung carcinoma tumor by ultraviolet irradiation. Cancer Res 45: 2560

  33. 33.

    Plescia OJ, Pontieri GM, Brown J, Racis S, Ippoliti F, Bellelli L, Sezzi ML, Lipari M (1984) Amplification by macrophages of prostaglandin-mediated immunosuppression in mice bearing syngeneic tumors. Prostaglandins Leukotrienes Med 16: 205

  34. 34.

    Puccetti P, Romani L, Fioretti MC (1987) Chemical xenozgenization of experimental tumors. Cancer Metast Rev 6: 93

  35. 35.

    SAS User's Guide (1985): Statistics, version 5 edition. Institute Inc., NC, USA ISBN, p 470

  36. 36.

    Shimizu Y, Fujiwara H, Ueda S, Wakamiya N, Kato S, Hamaoka T (1984) The augmentation of tumor-specific immunity by virus help. II. Enhanced induction of cytotoxic T lymphocyte and antibody response to tumor antigens by vaccinia virus reactive helper T cell. Eur J Immunol 14: 839

  37. 37.

    Van Pel A, Vessiere F, Boon T (1983) Protection against two spontaneous mouse leukemias confferred by immunogenic variants obtained by mutagenesis. J Exp Med 157: 1992

  38. 38.

    Yamaguchi H, Moriuchi T, Hosokawa M, Kobayashi H (1982) Increased or decreased immunogenicity of tumor-associated antigen according to the amount of virus-associated antigen in rat tumor cells infected with Friend virus. Cancer Immunol Immunother 12: 119

  39. 39.

    Yoshida MA, Sasaki M, Sugimura K, Kawachi T (1980) Cytogenic effects of quercetin on cultured mammalian cells. Proc Jap Acad 56(b): 443

  40. 40.

    Young MR, Hoover CS (1986) Inhibition of spleen cell cytotoxic capacity toward tumor by elevated prostaglandin E2 levels in mice bearing Lewis lung carcinoma. JNCI 77: 425

  41. 41

    Young MR, Knies S (1984) Prostaglandin E production by Lewis lung carcinoma: mechanism for tumor establishment in vivo. JNCI 72: 919

  42. 42.

    Young MR, Newby M (1986) Enhancement of Lewis lung carcinoma cell migration by prostaglandin E2 produced by macrophages. Cancer Res 46: 160

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Correspondence to Futoshi Okada.

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Okada, F., Hosokawa, M., Hasegawa, J. et al. Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: Diminution of tumorigenicity with a corresponding decrease in the production of prostaglandin E2 . Cancer Immunol Immunother 31, 358–364 (1990).

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  • Natural Killer Cell
  • Quercetin
  • Indomethacin
  • PGE2
  • Spleen Cell