Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The process of metastasis formation in cancer is not completely understood and is the main reason cancer therapies fail. Previously, we showed that dual liposomes simultaneously containing the hemostatic inhibitor, dipyridamole and the anticancer drug, perifosine potently inhibited metastasis, causing a 90% reduction in the number of lung metastases in a murine experimental metastasis model. To gain deeper insight into the mechanisms leading to the inhibition of metastasis by these dual liposomes, in the present study, the development of metastases by MT3 breast cancer cells in a mouse xenograft model was analyzed in more detail with regard to tumor cell settlement and metastatic growth. We found that the development of lung metastases by MT3 tumor cells is essentially dependent on the formation of fibrin clots as a precondition for the pulmonary arrest of tumor cells and the subsequent intravascular expansion of micrometastases before their invasion into the surrounding tissue.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fidler IJ (1990) Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 50:6130–6138

    CAS  PubMed  Google Scholar 

  2. Price JT, Thompson EW (2002) Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets 6:217–233

    Article  CAS  PubMed  Google Scholar 

  3. Tsuruo T, Fujita N (2008) Platelet aggregation in the formation of tumor metastasis. Proc Jpn Acad Ser B Phys Biol Sci 84:189–198

    Article  CAS  PubMed  Google Scholar 

  4. Khanna C, Hunter K (2005) Modeling metastasis in vivo. Carcinogenesis 26:513–523

    Article  CAS  PubMed  Google Scholar 

  5. Honn KV, Tang DG, Crissman JD (1992) Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 11:325–351

    Article  CAS  PubMed  Google Scholar 

  6. Felding-Habermann B (2003) Targeting tumor cell–platelet interaction in breast cancer metastasis. Pathophysiol Haemost Thromb 33(Suppl 1):56–58

    Article  PubMed  Google Scholar 

  7. Borsig L (2008) The role of platelet activation in tumor metastasis. Expert Rev Anticancer Ther 8:1247–1255

    Article  CAS  PubMed  Google Scholar 

  8. Chen M, Geng JG (2006) P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 54:75–84

    Article  CAS  Google Scholar 

  9. Borsig L, Wong R, Feramisco J et al (2001) Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci U S A 98:3352–3357

    Article  CAS  PubMed  Google Scholar 

  10. Kannagi R (1997) Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J 14:577–584

    Article  CAS  PubMed  Google Scholar 

  11. Trousseau A (1865) Phlegmasia alba dolens. In: Clinique Medicale de l’Hotel Dieu de Paris, vol 3. Paris, JB Balliere et Fils, Paris, France, pp 654–712

  12. Tohgo A, Tanaka NG, Ogawa H (1986) Platelet-aggregating activities of metastasizing tumor cells. IV. Effects of cell surface modification on thrombin generation, platelet aggregation and subsequent lung colonization. Invasion Metastasis 6:58–68

    CAS  PubMed  Google Scholar 

  13. Nieswandt B, Hafner M, Echtenacher B et al (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300

    CAS  PubMed  Google Scholar 

  14. Gupta GP, Massague J (2004) Platelets and metastasis revisited: a novel fatty link. J Clin Invest 114:1691–1693

    CAS  PubMed  Google Scholar 

  15. Al-Mehdi AB, Tozawa K, Fisher AB et al (2000) Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 6:100–102

    Article  CAS  PubMed  Google Scholar 

  16. Saiki I, Koike C, Obata A et al (1996) Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation. Int J Cancer 65:833–839

    Article  CAS  PubMed  Google Scholar 

  17. Kragh M, Loechel F (2005) Non-anti-coagulant heparins: a promising approach for prevention of tumor metastasis (review). Int J Oncol 27:1159–1167

    CAS  PubMed  Google Scholar 

  18. Hejna M, Raderer M, Zielinski CC (1999) Inhibition of metastases by anticoagulants. J Natl Cancer Inst 91:22–36

    Article  CAS  PubMed  Google Scholar 

  19. Bobek V, Kovarik J (2004) Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 58:213–219

    Article  CAS  PubMed  Google Scholar 

  20. Mancuso A, Sternberg CN (2006) New treatment approaches in metastatic renal cell carcinoma. Curr Opin Urol 16:337–341

    Article  PubMed  Google Scholar 

  21. Gosk S, Gottstein C, Bendas G (2005) Targeting of immunoliposomes to endothelial cells expressing VCAM: a future strategy in cancer therapy. Int J Clin Pharmacol Ther 43:581–582

    CAS  PubMed  Google Scholar 

  22. Kessner S, Krause A, Rothe U (2001) Investigation of the cellular uptake of E-selectin-targeted immunoliposomes by activated human endothelial cells. Biochim Biophys Acta 1514:177–190

    Article  CAS  PubMed  Google Scholar 

  23. Zeisig R, Stahn R, Wenzel K et al (2004) Effect of sialyl Lewis X-glycoliposomes on the inhibition of E-selectin-mediated tumour cell adhesion in vitro. Biochim Biophys Acta 1660:31–40

    Article  CAS  PubMed  Google Scholar 

  24. Keil C, Zeisig R, Fichtner I (2005) Effect of surface modified liposomes on the aggregation of platelets and tumor cells. Thromb Haemost 94:404–411

    CAS  PubMed  Google Scholar 

  25. Borsig L, Wong R, Hynes RO (2002) Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A 99:2193–2198

    Article  CAS  PubMed  Google Scholar 

  26. Wenzel J, Zeisig R, Fichtner I (2009) Inhibition of breast cancer metastasis by dual liposomes to disturb complex formation. Int J Pharm 370:121–128

    Article  CAS  PubMed  Google Scholar 

  27. Naundorf H, Rewasowa EC, Fichtner I (1992) Characterization of two human mammary carcinomas, MT-1 and MT-3, suitable for in vivo testing of ether lipids and their derivatives. Breast Cancer Res Treat 23:87–95

    Article  CAS  PubMed  Google Scholar 

  28. Cardinal DC, Flower RJ (1980) The electronic aggregometer: a novel device for assessing platelet behavior in blood. J Pharmacol Methods 3:135–158

    Article  CAS  PubMed  Google Scholar 

  29. Ottewell PD, Coleman RE, Holen I (2006) From genetic abnormality to metastases: murine models of breast cancer and their use in the development of anticancer therapies. Breast Cancer Res Treat 96:101–113

    Article  CAS  PubMed  Google Scholar 

  30. Fantozzi A, Christofori G (2006) Mouse models of breast cancer metastasis. Breast Cancer Res 8:212

    Article  PubMed  Google Scholar 

  31. Im JH, Fu W, Wang H et al (2004) Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 64:8613–8619

    Article  CAS  PubMed  Google Scholar 

  32. Gasic GJ (1984) Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 3:99–114

    Article  CAS  PubMed  Google Scholar 

  33. Beviglia L, Stewart GJ, Niewiarowski S (1995) Effect of four disintegrins on the adhesive and metastatic properties of B16F10 melanoma cells in a murine model. Oncol Res 7:7–20

    CAS  PubMed  Google Scholar 

  34. Oleksowicz L, Mrowiec Z, Schwartz E (1995) Characterization of tumor-induced platelet aggregation: the role of immunorelated GPIb and GPIIb/IIIa expression by MCF-7 breast cancer cells. Thromb Res 79:261–274

    Article  CAS  PubMed  Google Scholar 

  35. Palumbo JS, Talmage KE, Massari JV et al (2005) Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 105:178–185

    Article  CAS  PubMed  Google Scholar 

  36. Wong CW, Song C, Grimes MM et al (2002) Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 161:749–753

    PubMed  Google Scholar 

  37. Tao K, Fang M, Alroy J et al (2008) Imageable 4T1 model for the study of late stage breast cancer. BMC Cancer 8:228

    Article  PubMed  Google Scholar 

  38. DuPre’ SA, Hunter KW Jr (2007) Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors. Exp Mol Pathol 82:12–24

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Federal Ministry of Education and Research of Germany (Biochance PLUS program; PTJ-BIO/0313601). We thank Prof. M. van der Giet for supporting the Ph.D. work of J.W. at the Charite Berlin; M. Becker and M. Lemm (MDC Berlin-Buch) for excellent performance of the animal experiments; and Lipoid GmbH Ludwigshafen for providing us with egg phosphatidylcholine.

Conflict of interest statement

All authors confirm that they have no potential conflict of interest, including any financial, personal, or other relationships with other people or organizations within that could inappropriately influence (bias) their work.

Author information

Authors and Affiliations

  1. Max-Delbrück-Center for Molecular Medicine Berlin-Buch, R.-Rössle-Strasse 10, 13122, Berlin, Germany

    Jane Wenzel & Iduna Fichtner

  2. Experimental Pharmacology and Oncology Berlin-Buch GmbH (EPO GmbH), R.-Rössle-Strasse 10, 13122, Berlin, Germany

    Reiner Zeisig

  3. Charité, Medical Clinic IV, Nephrology, Campus Benjamin Franklin, Berlin, Germany

    Jane Wenzel

  4. Institute for Animal Pathology, Schönhauser Straße 62, 13127, Berlin, Germany

    Wolfram Haider

  5. Labor Sylvia Habedank, Postfach 49 01 52, 12281, Berlin, Germany

    Sylvia Habedank

Authors
  1. Jane Wenzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reiner Zeisig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wolfram Haider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sylvia Habedank
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Iduna Fichtner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jane Wenzel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wenzel, J., Zeisig, R., Haider, W. et al. Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation. Breast Cancer Res Treat 121, 13–22 (2010). https://doi.org/10.1007/s10549-009-0448-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-009-0448-4

Keywords

Search

Navigation