Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation
- 135 Downloads
- 6 Citations
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.
Keywords
Intravasal micrometastases Breast cancer Fibrin clot Platelet aggregation Liposomes Lung metastasesNotes
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.
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 50:6130–6138PubMedGoogle Scholar
- 2.Price JT, Thompson EW (2002) Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets 6:217–233CrossRefPubMedGoogle Scholar
- 3.Tsuruo T, Fujita N (2008) Platelet aggregation in the formation of tumor metastasis. Proc Jpn Acad Ser B Phys Biol Sci 84:189–198CrossRefPubMedGoogle Scholar
- 4.Khanna C, Hunter K (2005) Modeling metastasis in vivo. Carcinogenesis 26:513–523CrossRefPubMedGoogle Scholar
- 5.Honn KV, Tang DG, Crissman JD (1992) Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 11:325–351CrossRefPubMedGoogle Scholar
- 6.Felding-Habermann B (2003) Targeting tumor cell–platelet interaction in breast cancer metastasis. Pathophysiol Haemost Thromb 33(Suppl 1):56–58CrossRefPubMedGoogle Scholar
- 7.Borsig L (2008) The role of platelet activation in tumor metastasis. Expert Rev Anticancer Ther 8:1247–1255CrossRefPubMedGoogle 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) 54:75–84CrossRefGoogle 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 98:3352–3357CrossRefPubMedGoogle Scholar
- 10.Kannagi R (1997) Carbohydrate-mediated cell adhesion involved in hematogenous metastasis of cancer. Glycoconj J 14:577–584CrossRefPubMedGoogle 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 654–712Google Scholar
- 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 6:58–68PubMedGoogle 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 59:1295–1300PubMedGoogle Scholar
- 14.Gupta GP, Massague J (2004) Platelets and metastasis revisited: a novel fatty link. J Clin Invest 114:1691–1693PubMedGoogle 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 6:100–102CrossRefPubMedGoogle 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 65:833–839CrossRefPubMedGoogle Scholar
- 17.Kragh M, Loechel F (2005) Non-anti-coagulant heparins: a promising approach for prevention of tumor metastasis (review). Int J Oncol 27:1159–1167PubMedGoogle Scholar
- 18.Hejna M, Raderer M, Zielinski CC (1999) Inhibition of metastases by anticoagulants. J Natl Cancer Inst 91:22–36CrossRefPubMedGoogle Scholar
- 19.Bobek V, Kovarik J (2004) Antitumor and antimetastatic effect of warfarin and heparins. Biomed Pharmacother 58:213–219CrossRefPubMedGoogle Scholar
- 20.Mancuso A, Sternberg CN (2006) New treatment approaches in metastatic renal cell carcinoma. Curr Opin Urol 16:337–341CrossRefPubMedGoogle 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 43:581–582PubMedGoogle 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 1514:177–190CrossRefPubMedGoogle 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 1660:31–40CrossRefPubMedGoogle Scholar
- 24.Keil C, Zeisig R, Fichtner I (2005) Effect of surface modified liposomes on the aggregation of platelets and tumor cells. Thromb Haemost 94:404–411PubMedGoogle 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 99:2193–2198CrossRefPubMedGoogle Scholar
- 26.Wenzel J, Zeisig R, Fichtner I (2009) Inhibition of breast cancer metastasis by dual liposomes to disturb complex formation. Int J Pharm 370:121–128CrossRefPubMedGoogle 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 23:87–95CrossRefPubMedGoogle Scholar
- 28.Cardinal DC, Flower RJ (1980) The electronic aggregometer: a novel device for assessing platelet behavior in blood. J Pharmacol Methods 3:135–158CrossRefPubMedGoogle 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 96:101–113CrossRefPubMedGoogle Scholar
- 30.Fantozzi A, Christofori G (2006) Mouse models of breast cancer metastasis. Breast Cancer Res 8:212CrossRefPubMedGoogle 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 64:8613–8619CrossRefPubMedGoogle Scholar
- 32.Gasic GJ (1984) Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 3:99–114CrossRefPubMedGoogle 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 7:7–20PubMedGoogle 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 79:261–274CrossRefPubMedGoogle 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 105:178–185CrossRefPubMedGoogle 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 161:749–753PubMedGoogle Scholar
- 37.Tao K, Fang M, Alroy J et al (2008) Imageable 4T1 model for the study of late stage breast cancer. BMC Cancer 8:228CrossRefPubMedGoogle 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 82:12–24CrossRefPubMedGoogle Scholar