Skip to main content

Advertisement

SpringerLink
Log in

Empty liposomes induce antitumoral effects associated with macrophage responses distinct from those of the TLR1/2 agonist Pam3CSK4 (BLP)

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Liposomes are frequently used in cancer therapy to encapsulate and apply anticancer drugs. Here, we show that a systemic treatment of mice bearing skin tumors with empty phosphatidylcholine liposomes (PCL) resulted in inhibition of tumor growth, which was similar to that observed with the synthetic bacterial lipoprotein and TLR1/2 agonist Pam3CSK4 (BLP). Both compounds led to a substantial decrease of macrophages in spleen and in the tumor-bearing skin. Furthermore, both treatments induced the expression of typical macrophage markers in the tumor-bearing tissue. As expected, BLP induced the expression of the M1 marker genes Cxcl10 and iNOS, whereas PCL, besides inducing iNOS, also increased the M2 marker genes Arg1 and Trem2. In vitro experiments demonstrated that neither PCL nor BLP influenced proliferation or survival of tumor cells, whereas both compounds inhibited proliferation and survival and increased the migratory capacity of bone marrow-derived macrophages (BMDM). However, in contrast to BLP, PCL did not activate cytokine secretion and induced a different BMDM phenotype. Together, the data suggest that similar to BLP, PCL induce an antitumor response by influencing the tumor microenvironment, in particular by functional alterations of macrophages, however, in a distinct manner from those induced by BLP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine 1:297–315

    Article  PubMed  CAS  Google Scholar 

  2. Riaz M (1995) Review article: stability and uses of liposomes. Pak J Pharm Sci 8:69–79

    PubMed  CAS  Google Scholar 

  3. Schwendener RA (2007) Liposomes in biology and medicine. Adv Exp Med Biol 620:117–128

    Article  PubMed  Google Scholar 

  4. Alipour M, Smith MG, Pucaj K, Suntres ZE (2012) Acute toxicity study of liposomal antioxidant formulations containing N-acetylcysteine, alpha-tocopherol, and gamma-tocopherol in rats. J Liposome Res 22(2):158–167

    Google Scholar 

  5. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K et al (1991) Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88:11460–11464

    Article  PubMed  CAS  Google Scholar 

  6. van Rooijen N, van Nieuwmegen R (1980) Liposomes in immunology: multilamellar phosphatidylcholine liposomes as a simple, biodegradable and harmless adjuvant without any immunogenic activity of its own. Immunol Commun 9:243–256

    PubMed  Google Scholar 

  7. Takano S, Aramaki Y, Tsuchiya S (2003) Physicochemical properties of liposomes affecting apoptosis induced by cationic liposomes in macrophages. Pharm Res 20:962–968

    Article  PubMed  CAS  Google Scholar 

  8. Ma HM, Wu Z, Nakanishi H (2011) Phosphatidylserine-containing liposomes suppress inflammatory bone loss by ameliorating the cytokine imbalance provoked by infiltrated macrophages. Lab Invest 91:921–931

    Article  PubMed  CAS  Google Scholar 

  9. Zhang J, Fujii S, Wu Z, Hashioka S, Tanaka Y et al (2006) Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia. J Neuroimmunol 172:112–120

    Article  PubMed  CAS  Google Scholar 

  10. Graeser R, Bornmann C, Esser N, Ziroli V, Jantscheff P et al (2009) Antimetastatic effects of liposomal gemcitabine and empty liposomes in an orthotopic mouse model of pancreatic cancer. Pancreas 38:330–337

    Article  PubMed  CAS  Google Scholar 

  11. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  PubMed  CAS  Google Scholar 

  12. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612

    Article  PubMed  CAS  Google Scholar 

  13. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  PubMed  CAS  Google Scholar 

  14. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    Article  PubMed  CAS  Google Scholar 

  15. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  PubMed  CAS  Google Scholar 

  16. Ydens E, Cauwels A, Asselbergh B, Goethals S, Peeraer L et al (2012) Acute injury in the peripheral nervous system triggers an alternative macrophage response. J Neuroinflammation 9:176

    Article  PubMed  CAS  Google Scholar 

  17. Liew FY, Patel M, Xu D (2005) Toll-like receptor 2 signalling and inflammation. Ann Rheum Dis 64(Suppl 4):iv104–iv105

    Article  PubMed  CAS  Google Scholar 

  18. Zhang Y, Luo F, Cai Y, Liu N, Wang L et al (2011) TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells. J Immunol 186:1963–1969

    Article  PubMed  CAS  Google Scholar 

  19. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K et al (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281

    Article  PubMed  CAS  Google Scholar 

  20. Zibat A, Uhmann A, Nitzki F, Wijgerde M, Frommhold A et al (2009) Time-point and dosage of gene inactivation determine the tumor spectrum in conditional Ptch knockouts. Carcinogenesis 30:918–926

    Article  PubMed  CAS  Google Scholar 

  21. So PL, Langston AW, Daniallinia N, Hebert JL, Fujimoto MA et al (2006) Long-term establishment, characterization and manipulation of cell lines from mouse basal cell carcinoma tumors. Exp Dermatol 15:742–750

    Article  PubMed  CAS  Google Scholar 

  22. Francke A, Herold J, Weinert S, Strasser RH, Braun-Dullaeus RC (2011) Generation of mature murine monocytes from heterogeneous bone marrow and description of their properties. J Histochem Cytochem 59:813–825

    Article  PubMed  CAS  Google Scholar 

  23. Liu J, Buckley JM, Redmond HP, Wang JH (2010) ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance. J Immunol 184:5802–5808

    Article  PubMed  CAS  Google Scholar 

  24. Scheffel J, Regen T, Van Rossum D, Seifert S, Ribes S et al (2012) Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia. Glia 60:1930–1943

    Article  PubMed  Google Scholar 

  25. Rasmussen JW, Cello J, Gil H, Forestal CA, Furie MB et al (2006) Mac-1 + cells are the predominant subset in the early hepatic lesions of mice infected with Francisella tularensis. Infect Immun 74:6590–6598

    Article  PubMed  CAS  Google Scholar 

  26. Ferron M, Vacher J (2005) Targeted expression of cre recombinase in macrophages and osteoclasts in transgenic mice. Genesis 41:138–145

    Article  PubMed  CAS  Google Scholar 

  27. D’Ambrosio D, Panina-Bordignon P, Sinigaglia F (2003) Chemokine receptors in inflammation: an overview. J Immunol Methods 273:3–13

    Article  PubMed  Google Scholar 

  28. Zhao Q (2010) Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. J Leukoc Biol 88:41–55

    Article  PubMed  CAS  Google Scholar 

  29. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176:4894–4901

    PubMed  CAS  Google Scholar 

  30. Geutskens SB, Nikolic T, Dardenne M, Leenen PJ, Savino W (2004) Defective up-regulation of CD49d in final maturation of NOD mouse macrophages. Eur J Imun 34:3465–3476

    Article  CAS  Google Scholar 

  31. Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A (2000) The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J 19:3325–3336

    Article  PubMed  CAS  Google Scholar 

  32. Luster AD (2002) The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol 14:129–135

    Article  PubMed  CAS  Google Scholar 

  33. Deshmane SL, Kremlev S, Amini S, Sawaya BE (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 29:313–326

    Article  PubMed  CAS  Google Scholar 

  34. Murata M (2008) Activation of Toll-like receptor 2 by a novel preparation of cell wall skeleton from mycobacterium bovis BCG Tokyo (SMP-105) sufficiently enhances immune responses against tumors. Cancer Sci 99:1435–1440

    Article  PubMed  CAS  Google Scholar 

  35. Cheng N, Xia T, Han Y, He QJ, Zhao R et al (2011) Synergistic antitumor effects of liposomal honokiol combined with cisplatin in colon cancer models. Oncol Lett 2:957–962

    PubMed  CAS  Google Scholar 

  36. Sakakima Y, Hayakawa A, Nagasaka T, Nakao A (2007) Prevention of hepatocarcinogenesis with phosphatidylcholine and menaquinone-4: in vitro and in vivo experiments. J Hepatol 47:83–92

    Article  PubMed  CAS  Google Scholar 

  37. Fukunaga K, Hossain Z, Takahashi K (2008) Marine phosphatidylcholine suppresses 1,2-dimethylhydrazine-induced colon carcinogenesis in rats by inducing apoptosis. Nutr Res 28:635–640

    Article  PubMed  CAS  Google Scholar 

  38. Cheng Y, Zhao Q, Liu X, Araki S, Zhang S et al (2006) Phosphatidylcholine-specific phospholipase C, p53 and ROS in the association of apoptosis and senescence in vascular endothelial cells. FEBS Lett 580:4911–4915

    Article  PubMed  CAS  Google Scholar 

  39. Li H, Lee JH, Kim SY, Yun HY, Baek KJ et al (2011) Phosphatidylcholine induces apoptosis of 3T3-L1 adipocytes. J Biomed Sci 18:91

    Article  PubMed  Google Scholar 

  40. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS et al (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57–63

    Article  PubMed  CAS  Google Scholar 

  41. Harokopakis E, Hajishengallis G, Michalek SM (1998) Effectiveness of liposomes possessing surface-linked recombinant B subunit of cholera toxin as an oral antigen delivery system. Infect Immun 66:4299–4304

    PubMed  CAS  Google Scholar 

  42. Richards RL, Rao M, Wassef NM, Glenn GM, Rothwell SW et al (1998) Liposomes containing lipid A serve as an adjuvant for induction of antibody and cytotoxic T-cell responses against RTS, S malaria antigen. Infect Immun 66:2859–2865

    PubMed  CAS  Google Scholar 

  43. Faisal SM, Chen JW, McDonough SP, Chang CF, Teng CH et al (2011) Immunostimulatory and antigen delivery properties of liposomes made up of total polar lipids from non-pathogenic bacteria leads to efficient induction of both innate and adaptive immune responses. Vaccine 29:2381–2391

    Article  PubMed  CAS  Google Scholar 

  44. Laverman P, Dams ET, Storm G, Hafmans TG, Croes HJ et al (2001) Microscopic localization of PEG-liposomes in a rat model of focal infection. J Controlled Release 75:347–355

    Article  CAS  Google Scholar 

  45. De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23:277–286

    Article  PubMed  Google Scholar 

  46. Sonoki T, Nagasaki A, Gotoh T, Takiguchi M, Takeya M et al (1997) Coinduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide. J Biol Chem 272:3689–3693

    Article  PubMed  CAS  Google Scholar 

  47. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177:3520–3524

    PubMed  CAS  Google Scholar 

  48. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604

    Article  PubMed  CAS  Google Scholar 

  49. Carr MW, Roth SJ, Luther E, Rose SS, Springer TA (1994) Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A 91:3652–3656

    Article  PubMed  CAS  Google Scholar 

  50. Flaishon L, Becker-Herman S, Hart G, Levo Y, Kuziel WA et al (2004) Expression of the chemokine receptor CCR2 on immature B cells negatively regulates their cytoskeletal rearrangement and migration. Blood 104:933–941

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Susan Peter for excellent animal care and Anke Frommhold for technical assistance. The work is supported by the DFG (FOR942 HA 2197/5-2 to Heidi Hahn).

Conflict of interest

None

Author information

Author notes

  1. Tommy Regen

    Present address: Institute for Molecular Medicine, University of Mainz, Mainz, Germany

Authors and Affiliations

  1. Institute of Human Genetics, University Medical Center, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany

    Simone König & Heidi Hahn

  2. Department of Neuropathology, University Medical Center, Göttingen, Germany

    Tommy Regen & Uwe-Karsten Hanisch

  3. Department of Cellular and Molecular Immunology, University Medical Center, Göttingen, Germany

    Kai Dittmann, Michael Engelke & Jürgen Wienands

  4. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    Reto Schwendener

  5. Department of Hematology and Oncology, University Medical Center, Göttingen, Germany

    Tobias Pukrop

Authors
  1. Simone König
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tommy Regen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kai Dittmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Engelke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Wienands
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reto Schwendener
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Uwe-Karsten Hanisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tobias Pukrop
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Heidi Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heidi Hahn.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 201 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

König, S., Regen, T., Dittmann, K. et al. Empty liposomes induce antitumoral effects associated with macrophage responses distinct from those of the TLR1/2 agonist Pam3CSK4 (BLP). Cancer Immunol Immunother 62, 1587–1597 (2013). https://doi.org/10.1007/s00262-013-1444-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-013-1444-4

Keywords

Search

Navigation