A Possible Mechanism by Which Dietary Fat Can Alter Tumorigenesis: Lipid Modulation of Macrophage Function

  • Kent L. Erickson
  • Neil E. Hubbard
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 364)


Numerous expiremental and epidemiological studies hace provided evidence linking dietary fat with increased risk for breast cancer. Some epidemiological studies have reported a positive correlation between breast cancer and dietary fat intake1 while a few have reported that no correlation existed.2–5 In contrast, studies with animal models of mammary tumorigenesis are more consistent. In general, the studies in rodents showed that high levels of dietary fat to an increased incidence of spontaneous or carcinogen-induced breast tumors as compared to animals fed a moderate or low level of dietary fat.6 In addition, rodents fed saturated fats.7–8 Not only has dietary fat been linked to altered primary tumor growth, but it also appears to influence the process of metastasis.9 Since linoleic acid (18:2n-6) was the most abundant fatty acid found in many of the polyunsaturated vegetable oils numerous investigators hae suggested that it may be pivotal in the promotion of mammary tumorigenesis. The role of linoleic acid in increasing carcinogen-induced mammary tumor incidence10 as well as metastasis11 has been previously demonstrated.


Macrophage Function Mammary Tumorigenesis Tumoricidal Activity Murine Peritoneal Macrophage Dietary Polyunsaturated Fatty Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Prentice, R.L., Dietary fat reduction as a hypothesis for the prevention of postmenopausal breast cancer, and a discussion of hypothesis testing research strategies, in: Diet and Breast Cancer, E.K. Weisburger, ed., Plenum Press, New York (1994).Google Scholar
  2. 2.
    Willett, W.C., D.J. Hunter, M.J. Stampfer, G. Colditz, J.E. Manson, D. Spiegelman, B. Rosner, C.H. Hennekens, and R.E. Speizer, Dietary fat and fiber in relation to risk of breast cancer. An 8-year follow-up, JAMA 268:2037 (1992).PubMedCrossRefGoogle Scholar
  3. 3.
    Harris, J.R., M.E. Lippman, U. Veronesi, and W. Willett, Breast cancer (1), N. Engl. J. Med. 327:319 (1992).PubMedCrossRefGoogle Scholar
  4. 4.
    Harris, J.R., M.E. Lippman, U. Veronesi, and W. Willett, Breast cancer (2), N. Engl. J. Med. 327:390(1992).PubMedCrossRefGoogle Scholar
  5. 5.
    Harris, J.R., M.E. Lippman, U. Veronesi, and W. Willett, Breast cancer (3), N. Engl. J. Med. 327:473 (1992).PubMedCrossRefGoogle Scholar
  6. 6.
    Welsch, C.W., Enhancement of mammary tumorigenesis by dietary fat: review of potential mechanisms, Am. J. Clin. Nutr. 45:192 (1987).PubMedGoogle Scholar
  7. 7.
    Carroll, K.K. and G.J. Hopkins, Dietary polyunsaturated fat versus saturated fat in relation to mammary carcinogenesis, Lipids 14:155 (1979).PubMedCrossRefGoogle Scholar
  8. 8.
    Hillyard, L.A. and S. Abraham, Effect of dietary polyunsaturated fatty acids on growth of mammary adenocarcinomas in mice and rats, Cancer Res. 39:4430 (1979).PubMedGoogle Scholar
  9. 9.
    Erickson, K.L. and N.E. Hubbard, Dietary fat and tumor metastasis, Nutr. Rev. 48:6 (1990).PubMedCrossRefGoogle Scholar
  10. 10.
    Ip, C, C.A. Carter, and M.M. Ip, Requirement of essential fatty acid for mammary tumori-genesis in the rat, Cancer Res. 45:1997 (1985).PubMedGoogle Scholar
  11. 11.
    Hubbard, N.E. and K.L. Erickson, Enhancement of metastasis from a transplantable mouse mammary tumor by dietary linoleic acid, Cancer Res. 47:6171 (1987).PubMedGoogle Scholar
  12. 12.
    Erickson, K.L. and I.K. Thomas, Susceptibility of mammary tumor cells to complement-mediated cytolysis after in vitro orin vivo fatty acid manipulation, J. Natl. Cancer Inst. 75:333 (1985).PubMedGoogle Scholar
  13. 13.
    Erickson, K.L. and L.A. Schumacher, Lack of an influence of dietary fat on murine natural killer cell activity,J. Nutr. 119:1311 (1989).PubMedGoogle Scholar
  14. 14.
    Lokesh, B.R., H.L. Hsieh, and J.E. Kinsella, Peritoneal macrophages from mice fed dietary (n-3) polyunsaturated fatty acids secrete low levels of prostaglandins, J. Nutr. 116:2547 (1986).PubMedGoogle Scholar
  15. 15.
    Lokesh, B.R., J.M. Black, J.B. German, and J.E. Kinsella, Docosahexaenoic acid and other dietary polyunsaturated fatty acids suppress leukotriene synthesis by mouse peritoneal macrophages, Lipids 23:968 (1988).PubMedCrossRefGoogle Scholar
  16. 16.
    Broughton, K.S., J. Whelan, I. Hardardottir, and J.E. Kinsella, Effect of increasing the di-etary (n-3) to (n-6) polyunsaturated fatty acid ratio on murine liver and peritoneal cell fatty acids and eicosanoid formation, J. Nutr. 121:155 (1991).PubMedGoogle Scholar
  17. 17.
    Chapkin, R.S., S.D. Somers, and K.L. Erickson, Dietary manipulation of macrophage phos-pholipid classes: selective increase of dihomogammalinolenic acid, Lipids 23:766 (1988).PubMedCrossRefGoogle Scholar
  18. 18.
    Chapkin, R.S., N.E. Hubbard, D.K. Buckman, and K.L. Erickson, Linoleic acid metabolism in metastatic and nonmetastatic murine mammary tumor cells, Cancer Res. 49:4724 (1989).PubMedGoogle Scholar
  19. 19.
    Brenner, R.R., H. Garda, H. DeGremes, I. Dumm, and H. Pezzano, Early effects of EFA deficiency on the structure and enzymatic activity of rat liver microsomes, Prog. Lipid Res. 20:315 (1982).CrossRefGoogle Scholar
  20. 20.
    DeSchrijuer, R. and O.S. Privett, Effects of dietary long chain fatty acids on the biosynthesis of unsaturated fatty acids in the rat, J. Nutr. 112:619 (1982).Google Scholar
  21. 21.
    Adams, O., G. Wolfram, and N. Zollner, Prostaglandin formation in man during intake of different amounts of linoleic acids in diets, Ann. Nutr. Metab. 26:315 (1982).CrossRefGoogle Scholar
  22. 22.
    Dupont, J., Essential fatty acids and prostaglandins, Prev. Med. 16:485 (1987).PubMedCrossRefGoogle Scholar
  23. 23.
    Lands, W.E.M., Renewed questions about polyunsaturated fatty acids, Nutr. Rev. 44:189 (1986).PubMedCrossRefGoogle Scholar
  24. 24.
    Lokesh, B.R., J.M. Black, and J.E. Kinsella, The suppression of eicosanoid synthesis by peritoneal macrophages is influenced by the ratio of dietary docosahexaenoic acid to linoleic acid, Lipids 24:589 (1989).PubMedCrossRefGoogle Scholar
  25. 25.
    Kuwae, T., P.C. Schmid, S.B. Johnson, and H.H.O. Schmid, Differential turnover of phos-pholipid acyl groups in mouse peritoneal macrophages, J. Biol. Chem. 265:5002 (1990).PubMedGoogle Scholar
  26. 26.
    Hibbs, J.B., H.A. Chapman, and J.B. Weinberg, The macrophage as an antineoplastic sur-veillance cell: biological perspectives, J. Reticuloendothel Soc. 24:549 (1978).PubMedGoogle Scholar
  27. 27.
    Cleveland, R.P., M.S. Meltzer, and B. Zbar, Tumor cytotoxicity in vitro by macrophages from mice infected with Mycobacterium bovis strain BCG, J. Natl. Cancer Inst. 52:1887 (1974).PubMedGoogle Scholar
  28. 28.
    Adams, D.O. and T.J. Koerner, Gene regulation in macrophage development and activation, Year. Immunol. 4:159(1989).PubMedGoogle Scholar
  29. 29.
    Pace, J.L., S.W. Russell, B.A. Torres, H.M. Johnson, and P.W. Gray, Recombinant mouse γ interferon induces the priming step in macrophage activation for tumor cell killing, J. Immunol. 130:2011 (1983).PubMedGoogle Scholar
  30. 30.
    Schreiber, R.D., J.L. Pace, S.W. Russell, A. Altaian, and D.H. Katz, Macrophage-activating factor produced by a T cell hybridoma: physiochemical and biosynthetic resemblance to gamma-interferon, J. Immunol. 131:826 (1983).PubMedGoogle Scholar
  31. 31.
    Becton, D.L., D.O. Adams, and T.A. Hamilton, Characterization of protein kinase C activity in interferon gamma treated murine peritoneal macrophages, J. Cell. Physiol. 125:485 (1985).PubMedCrossRefGoogle Scholar
  32. 32.
    Adams, D.O. and T.A. Hamilton, The cell biology of macrophage activation, Annu. Rev. Immunol. 2:283 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    Nathan, C.F., Secretory products in cytotoxicity, in: Biological Response Mediators and Modulators, J.T. August, ed., Academic Press, New York (1983).Google Scholar
  34. 34.
    Marino, P.A. and D.O. Adams, Interaction of Bacillus Calmette—Guerin-activated macro-phages and neoplastic cells in vitro. I. Conditions of binding and its selectivity, Cell. Immunol. 54:11 (1980).PubMedCrossRefGoogle Scholar
  35. 35.
    Adams, D.O., Effector mechanisms of cytolytically activated macrophages. I. Secretion of neutral proteases and effect of protease inhibitors, J. Immunol. 124:286 (1980).PubMedGoogle Scholar
  36. 36.
    Adams, D.O., K.J. Kao, R. Farb, and S.V. Pizzo, Effector mechanisms of cytolytically acti-vated macrophages. II. Secretion of a cytolytic factor by activated macrophages and its relationship to secreted neutral proteases, J. Immunol. 124:293 (1980).PubMedGoogle Scholar
  37. 37.
    Hubbard, N.E., D. Lim, S.D. Somers, and K.L. Erickson, Effects of in vitro exposure to arachidonic acid on TNF-α production by murine peritoneal macrophages, J. Leukoc. Biol. 54:105 (1993).PubMedGoogle Scholar
  38. 38.
    Somers, S.D. and K.L. Erickson, Alteration of tumor necrosis factor-cc production by macrophages from mice fed diets high in eicosapentaenoic and docosahexaenoic fatty acids, Cell. Immunol. 153:287 (1994).PubMedCrossRefGoogle Scholar
  39. 39.
    Bang, H.O., J. Dyerberg, and N. Hjorne, The composition of food consumed by Greenland Eskimos, Acta. Med. Scand. 200:69 (1976).PubMedCrossRefGoogle Scholar
  40. 40.
    Whitaker, M.O., A. Wyche, F. Fitzpatrick, H. Sprecher, and P. Needleman, Triene prosta-glandins: prostaglandin D3 and icosapentaenoic acid as potential antithrombotic substanc-es, Proc. Natl. Acad. Sci. USA 76:5919 (1979).PubMedCrossRefGoogle Scholar
  41. 41.
    Dyerberg, J., H.O. Bang, E. Stoffersen, S. Moncada, and J.R. Vane, Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?, Lancet ii:117 (1978).CrossRefGoogle Scholar
  42. 42.
    Kremer, J.M., J. Bigauoette, A.V. Michalek, M.A. Timchalk, L. Lininger, R.I. Rynes, C. Huyck, J. Zieminski, and L.E. Bartholomew, Effects of manipulation of dietary fatty acids on clinical manifestations of rheumatoid arthritis, Lancet i:184 (1985).CrossRefGoogle Scholar
  43. 43.
    Prickett, J.D., D.E. Trentham, and D.R. Robinson, Dietary fish oil augments the induction of arthritis in rats immunized with type II collagen, J. Immunol. 132:725 (1984).PubMedGoogle Scholar
  44. 44.
    Leslie, C.A., W.A. Gonnerman, M.D. Ullman, K.C. Hayes, C Franzblau, and E.S. Cathcart, Dietary fish oil modulates macrophage fatty acids and decreases arthritis susceptibility in mice, J. Exp. Med. 162:1336 (1985).PubMedCrossRefGoogle Scholar
  45. 45.
    Somers, S.D., R.S. Chapkin, and K.L. Erickson, Alteration of in vitro murine peritoneal macrophage function by dietary enrichment with eicosapentaenoic and docosahexaenoic acids in menhaden fish oil, Cell. Immunol. 123:201 (1989).PubMedCrossRefGoogle Scholar
  46. 46.
    Hubbard, N.E., S.D. Somers, and K.L. Erickson, Effect of dietary fish oil on development and selected functions of murine inflammatory macrophages, J. Leukoc. Biol. 49:592 (1991).PubMedGoogle Scholar
  47. 47.
    Carswell, E.A., L.J. Old, R.L. Kassel, S. Green, N. Fiore, and B. Williamson, An endotoxin-induced serum factor that causes necrosis of tumors, Proc. Natl. Acad. Sci. USA72:3666 (1975).PubMedCrossRefGoogle Scholar
  48. 48.
    Tracey, K.J., B. Beutler, S.F. Lowry, J. Merryweather, S. Wolpe, I.W. Milsark, R.J. Hariri, TJ. Fahey III, A. Zentella, J.D. Albert, G.T. Shires, and A. Cerami, Shock and tissue injury induced by recombinant human cachectin, Science 234:470 (1986).PubMedCrossRefGoogle Scholar
  49. 49.
    Tracey, K.J., H. Wei, K.R. Manogue, Y. Fong, D.G. Hesse, H.T. Nguyen, G.C. Kuo, B. Beutler, R.S. Cotran, and A. Cerami, Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation, J. Exp. Med. 167:1211 (1988).PubMedCrossRefGoogle Scholar
  50. 50.
    Beutler, B. and A. Cerami, Tumor necrosis, cachexia, shock, and inflammation: a common mediator, Annu. Rev. Biochem. 57:505 (1988).PubMedCrossRefGoogle Scholar
  51. 51.
    Hardardottir, I. and J.E. Kinsella, Tumor necrosis factor production by murine resident peri-toneal macrophages is enhanced by dietary n-3 polyunsaturated fatty acids, Biochim. Biophys. Acta 1095:187 (1991).PubMedCrossRefGoogle Scholar
  52. 52.
    Vilcek, J. and T.H. Lee, Tumor necrosis factor, J. Biol. Chem. 266:7313 (1991).PubMedGoogle Scholar
  53. 53.
    Endres, S., R. Ghorbani, V.E. Kelley, K. Georgilis, G. Lonnemann, J. Vandermeer, J.G. Cannon, T.S. Rogers, M.S. Klempner, P.C. Weber, E.J. Schaefer, S.M. Wolff, and C.A. Dinarello, The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells, N. Engl. J. Med. 320:265 (1989).PubMedCrossRefGoogle Scholar
  54. 54.
    Kunkel, S.L., M. Spengler, G. Kwon, M.A. May, and D.G. Remick, Production and regula-tion of tumor necrosis factor alpha, Methods Achiev. Exp. Pathol. 13:240 (1988).PubMedGoogle Scholar
  55. 55.
    Kunkel, S.L., M. Spengler, M.A. May, R. Spengler, J. Larrick, and D. Remick, Prostaglan-din E2 regulates macrophage-derived tumor necrosis factor gene expression, J. Biol. Chem. 263:5380 (1988).PubMedGoogle Scholar
  56. 56.
    Braun, D.P., M.-C. Ahn, J.E. Harris, E. Chu, L. Casey, G. Wilbanks, and K.P. Siziopikou, Sensitivity of tumoricidal function in macrophages from different anatomical sites of cancer patients to modulation of arachidonic acid metabolism, Cancer Res. 53:3362 (1993).PubMedGoogle Scholar
  57. 57.
    Prpic, V., J.E. Weiel, S.D. Somers, J. DiGuiseppi, S.L. Gonias, S.V. Pizzo, T.A. Hamilton, B. Herman, and D.O. Adams, Effects of bacterial lipopolysaccharide on the hydrolysis of phosphatidylinositol-4,5 biphosphate in murine peritoneal macrophages, J. Immunol. 139:526 (1987).PubMedGoogle Scholar
  58. 58.
    Suk, K. and K.L. Erickson, Enhancement of BTG 1 gene expression by prostaglandin E2 in macrophages, Submitted for publication (1994).Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Kent L. Erickson
    • 1
  • Neil E. Hubbard
    • 1
  1. 1.Department of Cell Biology and Human AnatomyUniversity of California School of MedicineDavisUSA

Personalised recommendations