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. 1993 Mar;37(2):125–130. doi: 10.1007/BF01517045

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

G Heuff 1, H S A Oldenburg 1, H Boutkan 1, J J Visser 1, R H J Beelen 2, N Van Rooijen 2, C D Dijkstra 2, S Meyer 1,✉
PMCID: PMC11038189  PMID: 8319242

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.

Key words: Liposomes, (Dichloromethylene)bisphosphonate, Kupffer cells, Metastatic growth, Liver

References

  • 1.Balducci L, Hardy C. High proliferation of granulocyte-macrophage progenitors in tumour-bearing mice. Cancer Res. 1983;43:4643. [PubMed] [Google Scholar]
  • 2.Bottazzi B, Polentarutti N, Acero R, Balsari A, Boraschi D, Ghezzi P, Salmona M, Mantovani A. Regulation of the macrophage content of neoplasms by chemoattractants. Science. 1983;220:210. doi: 10.1126/science.6828888. [DOI] [PubMed] [Google Scholar]
  • 3.Boutkan H, De Graaf PW, Ruevekamp M, Ten Berg RGM. Determination of the liver tumour load in colonic carcinoma metastasizing to the liver: an experimental study in the rat. Surg Res Commun. 1988;3:319. [Google Scholar]
  • 4.Claassen I, Van Rooijen N, Claassen E. A new method for removal of mononuclear phagocytes from heterogenous cell population in vitro, using liposome encapsulated dichloromethylene diphosphonate. J Immunol Methods. 1990;134:153. doi: 10.1016/0022-1759(90)90376-7. [DOI] [PubMed] [Google Scholar]
  • 5.Collier DSJ, Pain JA, Wight DGD, Lovat P, Bailey ME. The Kupffer cell in experimental extrahepatic cholestasis in the rat: a light microscopy, immunohistochemical and electron microscopy study. J Pathol. 1986;150:187. doi: 10.1002/path.1711500307. [DOI] [PubMed] [Google Scholar]
  • 6.Daemen T. Activation of Kupffer cell tumouricidal activity by immunomodulators encapsulated in liposomes. Res Immunol. 1992;143:211. doi: 10.1016/s0923-2494(92)80168-k. [DOI] [PubMed] [Google Scholar]
  • 7.Dijkstra CD, Döpp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985;54:589. [PMC free article] [PubMed] [Google Scholar]
  • 8.Fidler IJ. Systemic macrophage activation with liposome entrapped immunomodulators for therapy of cancer metastasis. Res Immunol. 1992;143:199. doi: 10.1016/s0923-2494(92)80166-i. [DOI] [PubMed] [Google Scholar]
  • 9.Fleisch H. Biphosphanates: a new class of drugs in diseases of bone and calcium metabolism. Handb Exp Pharmacol. 1988;83:441. [Google Scholar]
  • 10.Huitinga I, Damoiseaux JGMC, Van Rooijen N, Döpp EA, Dijkstra CD. Liposome-mediated affection of monocytes. Immunobiology. 1992;185:11. doi: 10.1016/S0171-2985(11)80313-X. [DOI] [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. Elimination of macrophages with silica and asbestos. Methods Enzymol. 1984;108:325. doi: 10.1016/s0076-6879(84)08099-x. [DOI] [PubMed] [Google Scholar]
  • 13.Keepers YP, Pizao PE, Peters GJ, Van Ark-Otte J, Winograd B, Pinedo HM. Comparison of the sulforhodamine B protein and tetrazolium (MTT) assay for in vitro chemosensitivity testing. Eur J Cancer. 1991;27:897. doi: 10.1016/0277-5379(91)90142-z. [DOI] [PubMed] [Google Scholar]
  • 14.Kopper L, Van Hanh T, Lapis K. Experimental model for liver metastasis using Lewis lung tumour. J Cancer Res Clin Oncol. 1982;103:31. doi: 10.1007/BF00410303. [DOI] [PubMed] [Google Scholar]
  • 15.Lipton JH, Sach SC. Characterization of macrophage- and granulocyte-inducing proteins from normal and leukemic myeloid cells produced by Krebs ascites tumour. Biophys Acta. 1981;673:552. doi: 10.1016/0304-4165(81)90486-4. [DOI] [PubMed] [Google Scholar]
  • 16.Mantovani A. Tumour-associated macrophages. Curr Opin Immunol. 1990;2:689. doi: 10.1016/0952-7915(90)90031-b. [DOI] [PubMed] [Google Scholar]
  • 17.Munro I (ed) (1980) Bone-marrow origin of Kupffer cells. Lancet I:30 [PubMed]
  • 18.Norbury KC, Kripke ML. Ultra-violet-induced carcinogenesis in mice treated with silica, trypan blue or pyran copolymer. J Reticuloendothel Soc. 1979;26:827. [PubMed] [Google Scholar]
  • 19.Pearson HJ, Anderson J, Chamberlain J, Bell PRF. The effect of Kupffer cell stimulation or depression on the development of liver metastases in the rat. Cancer Immunol Immunother. 1986;23:214. doi: 10.1007/BF00205652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Phillips NC. Kupffer cells and liver metastasis. Cancer Metastasis Rev. 1989;8:231. doi: 10.1007/BF00047339. [DOI] [PubMed] [Google Scholar]
  • 21.Phillips NC, Tsao MS. Liposomal muramyl dipeptide therapy of experimental M5076 liver metastases in mice. Cancer Immunol Immunother. 1992;33:85. doi: 10.1007/BF01742534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Pinto AJ, Stewart D, Volkmann A, Jendrasiak G, Van Rooijen N, Morahan PS. Selective depletion of macrophages using toxins encapsulated in liposomes: effect on antimicrobial resistance. In: Lopez-Berestein G, Fidler I, editors. Liposomes in the therapy of infectious diseases and cancer. New York: Liss; 1989. p. 441. [Google Scholar]
  • 23.Pomeroy C, Filice GA. Effects of intravenous silica on the course ofNotocardia asteroides pneumonia. Infect Immun. 1988;56:2507. doi: 10.1128/iai.56.9.2507-2511.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Proffitt RT, Williams LE, Presant CA, Tin GW, Uliana JA, Gamble RC, Baldeschwieler JD. Liposomal blockade of the reticuloendothelial system: improved tumour imaging with small unilamellar vesicles. Science. 1983;220:502. doi: 10.1126/science.6836294. [DOI] [PubMed] [Google Scholar]
  • 25.Reed D, Burnham K. Tumour-associated macrophages share in vitro growth characteristics with resident but not elicited macrophages. J Leukocyte Biol. 1991;50:167. doi: 10.1002/jlb.50.2.167. [DOI] [PubMed] [Google Scholar]
  • 26.Shek PN, Lukovich S. The role of macrophages in promoting the antibody response mediated by liposome-associated protein antigens. Immunol Lett. 1982;5:305. doi: 10.1016/0165-2478(82)90118-3. [DOI] [PubMed] [Google Scholar]
  • 27.Skehan P, Storeng P, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bodesch H, Kenney S, Boyd MR. New colorimetric cytotoxicity assay for anticancer-drug screening. JNCI. 1990;82:1107. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  • 28.Stewart CC. Regulation of mononuclear phagocyte proliferation. In: Reichard SM, Filkins JP, editors. Reticulo-endothelial system. A comprehensive treatise, vol 7A. New York: Plenum; 1984. p. 37. [Google Scholar]
  • 29.Van der Meer JWM. Proliferation and differentiation of mononuclear phagocytes in vitro. In: van Furth R, editor. Mononuclear phagocytes. Characteristics, physiology and function. Philadelphia: Davis; 1985. p. 243. [Google Scholar]
  • 30.Van Rooijen N. The liposome mediated macrophage “suicide” technique. J Immunol. Methods. 1989;124:1. doi: 10.1016/0022-1759(89)90178-6. [DOI] [PubMed] [Google Scholar]
  • 31.Van Rooijen N, Claassen E. In vivo elimination of macrophages in spleen and liver, using liposome encapsulated drugs: methods and applications. In: Gregoriadis G, editor. Liposomes as drug carriers. Chichester, UK: Wiley; 1988. p. 131. [Google Scholar]
  • 32.Van Rooijen N, Van Nieuwmegen R. Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res. 1984;238:355. doi: 10.1007/BF00217308. [DOI] [PubMed] [Google Scholar]
  • 33.Van Rooijen N, Van Nieuwmegen R, Kamperdijk EWA. 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] 1985;49:375. doi: 10.1007/BF02912114. [DOI] [PubMed] [Google Scholar]
  • 34.Van Rooijen N, Kors N, Van der Ende M, Dijkstra CD. Depletion and repopulation of macrophages in spleen and liver of the rat after intravenous treatment with liposome encapsulated dichloromethylene diphosphonate. Cell Tissue Res. 1990;260:215. doi: 10.1007/BF00318625. [DOI] [PubMed] [Google Scholar]
  • 35.Vijayakumar RK, Muthukkaruppan VR. Analysis of carrageenan-induced suppression of antibody response. Immunology. 1990;70:181. [PMC free article] [PubMed] [Google Scholar]
  • 36.Wijfels JFAM, De Rover Z, Van Rooijen N, Kraal G, Beelen RHJ. Clonal expansion of bone marrow-derived macrophage cell lines, which can be repopulated in vivo. In: Imhoff B, editor. Lymphatic tissues and in-vivo immune responses. New York: Dekker; 1991. p. 815. [Google Scholar]
  • 37.Wirth JJ, Carney WP, Wheelock EF. The effect of particle size on the immunodepressive properties of silica. J Immunol Methods. 1980;32:357. doi: 10.1016/0022-1759(80)90028-9. [DOI] [PubMed] [Google Scholar]
  • 38.Wisse E. On the Kupffer cell origin of the Kupffer cells. Blood Cells. 1980;6:91. [Google Scholar]
  • 39.Zedick MS, Sternberg SS. A model system for studies of colon carcinogenesis: tumour induction by a single injection of methylazoxymethanol acetate. JNCI. 1974;53:1419. doi: 10.1093/jnci/53.5.1419. [DOI] [PubMed] [Google Scholar]

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