Expression and Anticoagulant Function of the Endothelial Cell Protein C Receptor (EPCR) in Cancer Cell Lines

Naoko Tsuneyoshi; Kenji Fukudome; Shin-ichiro Horiguchi; Xiaofen Ye; Miwako Matsuzaki; Masakazu Toi; Koji Suzuki; Masao Kimoto

doi:10.1055/s-0037-1615692

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2001; 85(02): 356-361
DOI: 10.1055/s-0037-1615692

Review Article

Schattauer GmbH

Expression and Anticoagulant Function of the Endothelial Cell Protein C Receptor (EPCR) in Cancer Cell Lines

Naoko Tsuneyoshi

¹Department of Immunology, Saga Medical School, Saga, Japan

,

Kenji Fukudome

¹Department of Immunology, Saga Medical School, Saga, Japan

⁵Department of Immunology

,

Shin-ichiro Horiguchi

³Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

,

Xiaofen Ye

¹Department of Immunology, Saga Medical School, Saga, Japan

,

Miwako Matsuzaki

²Department of Internal Medicine, Saga Medical School, Saga, Japan

,

Masakazu Toi

³Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

,

Koji Suzuki

⁴Department of Molecular Pathobiology, Mie University School of Medicine, Tsu-City, Mie, Japan

,

Masao Kimoto

¹Department of Immunology, Saga Medical School, Saga, Japan

› Author Affiliations

Abstract

Summary

Induction of procoagulant factors in malignant cells is considered to be the major cause of coagulation disorders in cancer. Thrombomodulin (TM), a negative regulator of coagulation was also found to be expressed in cancer cells. We report here evidence for another anticoagulant, the endothelial cell protein C receptor (EPCR), in cancer cells. EPCR was detected in several cell lines derived from various types of cancer. Significant levels of protein C (PC) activation were detected only with cell lines expressed both EPCR and TM. Anti-EPCR monoclonal antibodies (mAbs) specifically inhibited the activation. Thus, EPCR function appears to be important for PC activation by cancer cells. In addition, we detected EPCR expression in tumor cells from breast cancer patients, with an extremely high frequency. EPCR function may contribute to progression or pathogenesis of some types of cancer, and may explain the complexity of coagulopathy in cancer patients.

Keywords

Protein C - endothelial cell - receptor - glioblastoma - leukemia

Full Text

References

References
1 Sallah S. Selected coagulation disorders associated with cancer. In Vivo 1998; 12: 671-3.
2 Francis JL, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy. Semin Thromb Hemost 1998; 24: 93-109.
3 Rodrigues-Erdmann F. Bleeding due to increased intravascular blood coagulation. N Engl J Med 1970; 237: 1370-8.
4 Morrissey JH, Fakhrai H, Edgington TS. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell 1987; 50: 129-35.
5 Spicer EK, Horton R, Bloem L, Bach R, Williams KR, Guha A, Kraus J, Lin TC, Nemerson Y, Konigsberg WH. Isolation of cDNA clones coding for human tissue factor. Proc Natl Acad Sci USA 1987; 84: 5148-52.
6 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 1-8.
7 Rao LV. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-66.
8 Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant. Biochemistry 1985; 24: 5558-67.
9 Reitsma PH. Protein C, deficiency: from gene defects to disease. Thromb Haemost 1997; 78: 344-50.
10 Esmon CT, Stenflo J, Suttie JW. A new vitamin K-dependent protein. A phospholipid-binding zymogen of a serine esterase. J Biol Chem 1976; 251: 3052-6.
11 Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci USA 1981; 78: 2249-52.
12 Jackman RW, Beeler DL, VanDeWater L, Rosenberg RD. Characterization of a thrombomodulin cDNA reveals structural similarity to the low density lipoprotein receptor. Proc Natl Acad Sci USA 1986; 83: 8834-8.
13 Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, Kawahara S, Honda G, Yamamoto S, Horiguchi S. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 1987; 6: 1891-7.
14 Fukudome K, Esmon CT. Identification, cloning and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem 1994; 269: 26486-91.
15 Fukudome K, Ye X, Tsuneyoshi N, Tokunaga O, Sugawara K, Mizokami H, Kimoto M. Activation mechanism of anticoagulant protein C in large blood vessels involving the endothelial cell protein C receptor. J Exp Med 1998; 187: 1029-35.
16 Imashuku S, Inui A, Nakamura T, Tanaka J, Miyake S. Catecholamine metabolism in tissue culture cells of a neuroblastoma. J Clin Endocrinol Metab 1973; 36: 931-6.
17 Gilbert F, Balaban G, Moorhead P, Bianchi D, Schlesinger H. Abnormalities of chromosome 1p in human neuroblastoma tumors and cell lines. Cancer Genet Cytogenet 1982; 7: 33-42.
18 Palacios R, Steinmetz M. IL-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell 1985; 41: 727-34.
19 Kimura G, Itagaki A, Summers J. Rat cell line 3y1 and its virogenic polyomaand sv40-transformed derivatives. Int J Cancer 1975; 15: 694-706.
20 Hayashi T, Suzuki K. Monoclonal antibodies for human thrombomodulin which recognize binding sites for thrombin and protein C. J Biochem (Tokyo) 1990; 108: 874-8.
21 Sigvardsson M, O’Riordan M, Grosschedl R. EBF and E47 collaborate to induce expression of the endogenous immunoglobulin surrogate light chain genes. Immunity 1997; 7: 25-36.
22 Ye X, Fukudome K, Tsuneyoshi N, Satoh T, Tokunaga O, Sugawara K, Mizokami H, Kimoto M. The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins and capillaries. Biochem Biophys Res Commun 1999; 259: 671-7.
23 Grey ST, Hancock WW. A physiologic anti-inflammatory pathway based on thrombomodulin expression and generation of activated protein C by human mononuclear phagocytes. J Immunol 1996; 156: 2256-63.
24 Koyama T, Hirosawa S, Kawamata N, Tohda S, Aoki N. All-trans retinoic acid upregulates thrombomodulin and downregulates tissue-factor expression in acute promyelocytic leukemia cells. Blood 1994; 84: 3001-9.
25 Obeso J, Weber J, Auerbach R. A hemangioendothelioma-derived cell line: its use as a model for the study of endothelial cell biology. Lab Invest 1990; 63: 259-69.
26 Maruno M, Yoshimine T, Isaka T, Kuroda R, Ishii H, Hayakawa T. Expression of thrombomodulin in astrocytomas of various malignancy and in gliotic and normal brains. J Neurooncol 1994; 19: 155-60.
27 Borrow J, Goddard AD, Sheer D, Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 1990; 249: 1577-80.
28 de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990; 347: 558-61.
29 Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant trans-location in acute promyelocytic leukaemia. Nat Genet 1997; 17: 109-13.
30 Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, Mencarelli A, Grignani F, Peschle C, Nicoletti I. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993; 74: 423-31.
31 Koeffler HP. Induction of differentiation of human acute myelogenous leukemia cells. Blood 1983; 62: 709-21.
32 Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567-72.
33 Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood 1992; 79: 543-53.
34 Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood 1998; 91: 3093-102.
35 Weiler-Guettler H, Yu K, Soff G, Gudas LJ, Rosenberg RD. Thrombomodulin gene regulation by cAMP and retinoic acid in F9 embryonal carcinoma cells. Proc Natl Acad Sci USA 1992; 89: 2155-9.
36 Horie S, Kizaki K, Ishii H, Kazama M. Retinoic acid stimulates expression of thrombomodulin, a cell surface anticoagulant glycoprotein, on human endothelial cells. Differences between up-regulation of thrombomodulin by retinoic acid and cyclic AMP. Biochem J 1992; 281: 149-54.
37 Saito T, Koyama T, Nagata K, Kamiyama R, Hirosawa S. Anticoagulant effects of retinoic acids on leukemia cells. Blood 1996; 87: 657-65.
38 Hirokawa K, Aoki N. Up-regulation of thrombomodulin in human umbilical vein endothelial cells in vitro. J Biochem (Tokyo) 1990; 108: 839-45.
39 Kapiotis S, Besemer J, Bevec D, Valent P, Bettelheim P, Lechner K, Speiser W. Interleukin-4 counteracts pyrogen-induced downregulation of thrombomodulin in cultured human vascular endothelial cells. Blood 1991; 78: 410-5.
40 Nguyen M, Arkell J, Jackson CJ. Activated protein C directly activates human endothelial gelatinase A. J Biol Chem 2000; 275: 9095-8.