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Enhanced tumour growth in the rat liver after selective elimination of Kupffer cells

  • Original Articles
  • Liposomes, (Dichloromethylene)bisphosphonate, Kupffer Cells, Metastatic Growth, Liver
  • Published:
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Abstract

The evidence that Kupffer cells are capable of controlling metastatic growth in the liver in vivo is largely circumstantial. The best approach when studying natural cytotoxicity activities of Kupffer cells is to investigate the effect of Kupffer cell elimination on tumour growth. Until now it has not been possible to eliminate Kupffer cells without affecting other cell populations. We have recently developed a new method to eliminate Kupffer cells selectively: intravenous injection of liposome-encapsulated (dichloromethylene)bisphosphonate (Cl2MDP-liposomes) leads to effective elimination of all Kypffer cells, without affecting non-phagocytic cells. Wag/Rij rats were injected with Cl2MDP-liposomes. After 48 h, rats were inoculated with syngeneic CC531 colon carcinoma cells by injection in the portal system. The results show a strongly enhanced tumour growth in the liver of the Cl2MDP-liposometreated rats. In these animals, livers were almost completely replaced by tumour and had increased in weight, whereas in the control groups only a few (four to eight) small (1-mm) tumour nodules were found. These data show that selective elimination of Kupffer cells results in enhanced tumour growth in the liver, implying that Kupffer cells play a crucial role in controlling tumour growth in the liver.

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References

  1. Balducci L, Hardy C (1983) High proliferation of granulocyte-macrophage progenitors in tumour-bearing mice. Cancer Res 43:4643

    PubMed  Google Scholar 

  2. Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A (1983) Regulation of the macrophage content of neoplasms by chemoattractants. Science 220:210

    PubMed  Google Scholar 

  3. Boutkan H, De Graaf PW, Ruevekamp, M, Ten Berg RGM (1988) Determination of the liver tumour load in colonic carcinoma metastasizing to the liver: an experimental study in the rat. Surg Res Commun 3:319

    Google Scholar 

  4. Claassen I, Van Rooijen N, ClaassenE (1990) A new method for removal of mononuclear phagocytes from heterogenous cell population in vitro, using liposome encapsulated dichloromethylene diphosphonate. J Immunol Methods 134:153

    PubMed  Google Scholar 

  5. Collier DSJ, Pain JA, Wight DGD, Lovat P, Bailey ME (1986) The Kupffer cell in experimental extrahepatic cholestasis in the rat: a light microscopy, immunohistochemical and electron microscopy study. J Pathol 150:187

    PubMed  Google Scholar 

  6. Daemen T (1992) Activation of Kupffer cell tumouricidal activity by immunomodulators encapsulated in liposomes. Res Immunol 143:211

    PubMed  Google Scholar 

  7. Dijkstra CD, Döpp EA, Joling P, Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54:589

    PubMed  Google Scholar 

  8. Fidler IJ (1992) Systemic macrophage activation with liposome entrapped immunomodulators for therapy of cancer metastasis. Res Immunol 143:199

    PubMed  Google Scholar 

  9. Fleisch H (1988) Biphosphanates: a new class of drugs in diseases of bone and calcium metabolism. Handb Exp Pharmacol 83:441

    Google Scholar 

  10. Huitinga I, Damoiseaux JGMC, Van Rooijen N, Döpp EA, Dijkstra CD (1992) Liposome-mediated affection of monocytes. Immunobiology 185:11

    PubMed  Google Scholar 

  11. Juliano RL (1982) Liposomes and the reticuloendothelial system: interactions of liposomes with macrophages and behaviour of liposomes in vivo. In: Gregoriadis G, Senior J, Trouet A (eds) Targeting of drugs. p 285

  12. Kagan E, Hartmann DP (1984) Elimination of macrophages with silica and asbestos. Methods Enzymol 108:325

    PubMed  Google Scholar 

  13. Keepers YP, Pizao PE, Peters GJ, Van Ark-Otte J, Winograd B, Pinedo HM (1991) Comparison of the sulforhodamine B protein and tetrazolium (MTT) assay for in vitro chemosensitivity testing. Eur J Cancer 27:897

    PubMed  Google Scholar 

  14. Kopper L, Van Hanh T, Lapis K (1982) Experimental model for liver metastasis using Lewis lung tumour. J Cancer Res Clin Oncol 103:31

    PubMed  Google Scholar 

  15. Lipton JH, Sach SC (1981) Characterization of macrophage- and granulocyte-inducing proteins from normal and leukemic myeloid cells produced by Krebs ascites tumour. Biophys Acta 673:552

    Google Scholar 

  16. Mantovani A (1990) Tumour-associated macrophages. Curr Opin Immunol 2:689

    Google Scholar 

  17. Munro I (ed) (1980) Bone-marrow origin of Kupffer cells. Lancet I:30

  18. Norbury KC, Kripke ML (1979) Ultra-violet-induced carcinogenesis in mice treated with silica, trypan blue or pyran copolymer. J Reticuloendothel Soc 26:827

    PubMed  Google Scholar 

  19. Pearson HJ, Anderson J, Chamberlain J, Bell PRF (1986) The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat. Cancer Immunol Immunother 23:214

    PubMed  Google Scholar 

  20. Phillips NC (1989) Kupffer cells and liver metastasis. Cancer Metastasis Rev 8:231

    PubMed  Google Scholar 

  21. Phillips NC, Tsao MS (1992) Liposomal muramyl dipeptide therapy of experimental M5076 liver metastases in mice. Cancer Immunol Immunother 33:85

    Google Scholar 

  22. Pinto AJ, Stewart D, Volkmann A, Jendrasiak G, Van Rooijen N, Morahan PS (1989) Selective depletion of macrophages using toxins encapsulated in liposomes: effect on antimicrobial resistance. In: Lopez-Berestein G, Fidler I (eds) Liposomes in the therapy of infectious diseases and cancer. Liss, New York, p 441

    Google Scholar 

  23. Pomeroy C, Filice GA (1988) Effects of intravenous silica on the course ofNotocardia asteroides pneumonia. Infect Immun 56:2507

    PubMed  Google Scholar 

  24. Proffitt RT, Williams LE, Presant CA, Tin GW, Uliana JA, Gamble RC, Baldeschwieler JD (1983) Liposomal blockade of the reticuloendothelial system: improved tumour imaging with small unilamellar vesicles. Science 220:502

    PubMed  Google Scholar 

  25. Reed D, Burnham K (1991) Tumour-associated macrophages share in vitro growth characteristics with resident but not elicited macrophages. J Leukocyte Biol 50:167

    PubMed  Google Scholar 

  26. Shek PN, Lukovich S (1982) The role of macrophages in promoting the antibody response mediated by liposome-associated protein antigens. Immunol Lett 5:305

    PubMed  Google Scholar 

  27. Skehan P, Storeng P, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bodesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. JNCI 82:1107

    PubMed  Google Scholar 

  28. Stewart CC (1984) Regulation of mononuclear phagocyte proliferation. In: Reichard SM, Filkins JP (eds) Reticulo-endothelial system. A comprehensive treatise, vol 7A: Plenum, New York, p 37

    Google Scholar 

  29. Van der Meer JWM (1985) Proliferation and differentiation of mononuclear phagocytes in vitro. In: van Furth R (ed) Mononuclear phagocytes. Characteristics, physiology and function. Davis, Philadelphia, p. 243

    Google Scholar 

  30. Van Rooijen N (1989) The liposome mediated macrophage “suicide” technique. J Immunol. Methods 124:1

    PubMed  Google Scholar 

  31. Van Rooijen N, Claassen E (1988) In vivo elimination of macrophages in spleen and liver, using liposome encapsulated drugs: methods and applications. In: Gregoriadis G (ed) Liposomes as drug carriers. Wiley, Chichester, UK, p 131

    Google Scholar 

  32. Van Rooijen N, Van Nieuwmegen R (1984) Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res 238:355

    PubMed  Google Scholar 

  33. Van Rooijen N, Van Nieuwmegen R, Kamperdijk EWA (1985) Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. Ultrastructural aspects of elimination of marginal zone macrophages. Virchows Arch [B] 49:375

    Google Scholar 

  34. Van Rooijen N, Kors N, Van der Ende M, Dijkstra CD (1990) Depletion and repopulation of macrophages in spleen and liver of the rat after intravenous treatment with liposome encapsulated dichloromethylene diphosphonate. Cell Tissue Res 260:215

    PubMed  Google Scholar 

  35. Vijayakumar RK, Muthukkaruppan VR (1990) Analysis of carrageenan-induced suppression of antibody response. Immunology 70:181

    PubMed  Google Scholar 

  36. Wijfels JFAM, De Rover Z, Van Rooijen N, Kraal G, Beelen RHJ (1991) Clonal expansion of bone marrow-derived macrophage cell lines, which can be repopulated in vivo. In: Imhoff B (ed) Lymphatic tissues and in-vivo immune responses. Dekker, New York, p 815

    Google Scholar 

  37. Wirth, JJ, Carney WP, Wheelock EF (1980) The effect of particle size on the immunodepressive properties of silica. J Immunol Methods 32:357

    PubMed  Google Scholar 

  38. Wisse E (1980) On the Kupffer cell origin of the Kupffer cells. Blood Cells 6:91

    Google Scholar 

  39. Zedick MS, Sternberg SS (1974) A model system for studies of colon carcinogenesis: tumour induction by a single injection of methylazoxymethanol acetate. JNCI 53:1419

    PubMed  Google Scholar 

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Heuff, G., Oldenburg, H.S.A., Boutkan, H. et al. Enhanced tumour growth in the rat liver after selective elimination of Kupffer cells. Cancer Immunol Immunother 37, 125–130 (1993). https://doi.org/10.1007/BF01517045

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  • DOI: https://doi.org/10.1007/BF01517045

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