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01.07.2013 | Original Article

The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone

verfasst von: Kunihiro Asanuma, Hiroki Wakabayashi, Takayuki Okamoto, Yumiko Asanuma, Nobuyuki Akita, Tomoaki Yoshikawa, Tatsuya Hayashi, Akihiko Matsumine, Atsumasa Uchida, Akihiro Sudo

Erschienen in: Breast Cancer | Ausgabe 3/2013

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Abstract

Background

Breast cancer has the potential to metastasize to bone, causing debilitating symptoms. Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well established. To elucidate the efficacy of the thrombin inhibitor, argatroban, on bone metastasis, we investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban.

Methods

MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium. MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days. After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography.

Results

TF activity and VEGF secretion were upregulated by thrombin. Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin. In vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (P < 0.05).

Conclusions

Thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to reexpress TF. These results indicate that inhibition of thrombin is of great value in suppression of tumor metastasis. Argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has antimetastatic effects in vivo.

Gordon SG. Cancer cell procoagulants and their role in malignant disease. Semin Thromb Hemost. 1992;18(4):424–33.CrossRefPubMed

Rickles FR, Edwards RL. Activation of blood coagulation in cancer: trousseau’s syndrome revisited. Blood. 1983;62(1):14.PubMed

Rao LV. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev. 1992;11(3–4):249.PubMed

Murray JC. Coagulation and cancer. Br J Cancer. 1991;64(3):422–4.CrossRefPubMed

Costantini V, Zacharski LR. Fibrin and cancer. Thromb Haemost. 1993;69(5):406–14.PubMed

Nierodzik MLR, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res. 1992;52(12):3267–72.PubMed

Zain J, Huang YQ, Feng XS, Nierodzik ML, Li JJ, Karpatkin S. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood. 2000;95(10):3133.PubMed

Henrikson KP, Salazar SL, Fenton JW, Pentecost BT. Role of thrombin receptor in breast cancer invasiveness. Br J Cancer. 1999;79(3–4):401–6.CrossRefPubMed

Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginzburg Y, et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med. 1998;4(8):909–14.CrossRefPubMed

10.

Liu Y, Mueller BM. Protease-activated receptor-2 regulates vascular endothelial growth factor expression in MDA-MB-231 cells via MAPK pathways. Biochem Biophys Res Commun. 2006;344(4):1263–70.CrossRefPubMed

11.

BelAiba RS, Djordjevic T, Bonello S, Artunc F, Lang F, Hess J, et al. The serum- and glucocorticoid-inducible kinase Sgk-1 is involved in pulmonary vascular remodeling: role in redox-sensitive regulation of tissue factor by thrombin. Circ Res. 2006;98(6):828–36.CrossRefPubMed

12.

Escolar G, Bozzo J, Maragall S. Argatroban: a direct thrombin inhibitor with reliable and predictable anticoagulant actions. Drugs Today. 2006;42(4):223–36.CrossRefPubMed

13.

Asanuma K, Wakabayashi H, Hayashi T, Okuyama N, Seto M, Matsumine A, et al. Thrombin inhibitor, argatroban, prevents tumor cell migration and bone metastasis. Oncology. 2004;67(2):166–73.CrossRefPubMed

14.

Deguchi H, Takeya H, Wada H, Gabazza EC, Hayashi N, Urano H, et al. Dilazep, an antiplatelet agent, inhibits tissue factor expression in endothelial cells and monocytes. Blood. 1997;90(6):2345–56.PubMed

15.

Ollivier V, Chabbat J, Herbert JM, Hakim J, De Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa. Arterioscler Thromb Vasc Biol. 2000;20:1374–81.CrossRefPubMed

16.

Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer. 2000;83(2):164–70.CrossRefPubMed

17.

Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci. 1995;92(18):8205–9.CrossRefPubMed

18.

Booden MA, Eckert LB, Der CJ, Trejo JA. Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion. Mol Cell Biol. 2004;24(5):1990–9.CrossRefPubMed

19.

Liu J, Schuff-Werner P, Steiner M. Thrombin/thrombin receptor (PAR-1)-mediated induction of IL-8 and VEGF expression in prostate cancer cells. Biochem Biophys Res Commun. 2006;343(1):183–9.CrossRefPubMed

20.

Ge L, Shenoy SK, Lefkowitz RJ, DeFea K. Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2. J Biol Chem. 2004;279(53):55419–24.CrossRefPubMed

21.

Palumbo JS, Kombrinck KW, Drew AF, Grimes TS, Kiser JH, Degen JL, et al. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood. 2000;96(10):3302–9.PubMed

22.

Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.CrossRefPubMed

23.

Harris AL, Zhang H, Moghaddam A, Fox S, Scott P, Pattison A, et al. Breast cancer angiogenesis new approaches to therapy via antiangiogenesis, hypoxic activated drugs, and vascular targeting. Breast Cancer Res Treat. 1996;38(1):97–108.CrossRefPubMed

24.

Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, et al. Breast carcinoma vascular density determined using CD105 antibody correlates with tumor prognosis 1. Cancer Res. 1999;59(4):856–61.PubMed

25.

Goede V, Fleckenstein G, Dietrich M, Osmers RGW, Kuhn W, Augustin HG. Prognostic value of angiogenesis in mammary tumors. Anticancer Res. 1998;18(3C):2199–202.

26.

Heimann R, Ferguson D, Gray S, Hellman S. Assessment of intratumoral vascularization (angiogenesis) in breast cancer prognosis. Breast Cancer Res Treat. 1998;52:147–58.CrossRefPubMed

27.

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306–9.CrossRefPubMed

28.

Sachdev JC, Jahanzeb M. Evolution of bevacizumab-based therapy in the management of breast cancer. Clin Breast Cancer. 2008;8(5):402–10.CrossRefPubMed

29.

Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459.CrossRefPubMed

30.

Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, et al. Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther. 2009;8(7):1761.CrossRefPubMed

31.

Mohle R, Green D, Moore MAS, Nachman RL, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Natl Acad Sci. 1997;94:663–8.CrossRef

32.

Schulze EB, Hedley BD, Goodale D, Postenka CO, Al-Katib W, Tuck AB, et al. The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms. Breast Cancer Res Treat. 2008;112(2):243–54.CrossRefPubMed

Titel: The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone
verfasst von: Kunihiro Asanuma
Hiroki Wakabayashi
Takayuki Okamoto
Yumiko Asanuma
Nobuyuki Akita
Tomoaki Yoshikawa
Tatsuya Hayashi
Akihiko Matsumine
Atsumasa Uchida
Akihiro Sudo
Publikationsdatum: 01.07.2013
Verlag: Springer Japan
Erschienen in: Breast Cancer / Ausgabe 3/2013
Print ISSN: 1340-6868
Elektronische ISSN: 1880-4233
DOI: https://doi.org/10.1007/s12282-012-0334-5

Springer Medizin

The thrombin inhibitor, argatroban, inhibits breast cancer metastasis to bone