Abstract
Although the involvement of soluble and matrix-immobilized proteases in tumor cell invasion and metastasis is well recognized, the role of proteolytically activated cell surface receptors has not been elucidated. We report here that thrombin receptor, a member of the protease-activated receptor family, is preferentially expressed in highly metastatic human breast carcinoma cell lines and breast carcinoma biopsy specimens. Introduction of thrombin receptor antisense cDNA considerably inhibited the invasion of metastatic breast carcinoma cells in culture through a reconstituted basement membrane. During placental implantation of the human embryo, thrombin receptor is transiently expressed in the invading cytotrophoblasts. These results emphasize the involvement of thrombin receptor in cell invasion associated with tumor progression and normal embryonic development.
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References
Redman, C.W.G. Cytotrophoblast: Markers of disguise. Nature Med. 3, 610–611 (1997).
Zetter, B.R. The cellular basis of site-specific tumor metastasis. N. Engl. J. Med. 322, 605–612 (1990).
Rusciano, D. & Burger, M.M. Why do cancer cells metastasize into particular organs? Bioessays 14, 185–194 (1992).
Liotta, L., Rao, C.N. & Wewer, U.M. Biochemical interaction of tumor cells with the basement membrane. Ann. Rev. Biochem. 55, 1037–1057 (1986).
Lester, B.R. & McCarthy, J.B. Tumor cell adhesion to the extracellular matrix and signal transduction mechanisms implicated in tumor cell motility, invasion, and metastasis. Cancer Metastasis Rev. 11, 31–44 (1992).
Ruoslahti, E. Control of cell motility and tumor invasion by extracellular matrix interactions. Br. J. Cancer 66, 239–242 (1992).
Montgomery, A.M.P., Reisfled, R.A. & Cheresh, D.A. Integrin αvβ3 rescues melanoma cells from apoptosis in three dimensional dermal collagen. Proc. Natl. Acad. Sci. USA 91, 8856–8860 (1994).
Blasi, F. Urokinase and urokinase receptor: a paracrine/autocrine system regulating cell migration and invasion. Bioessays 15, 105–111 (1993).
Vu, T.-K., Hung, H.D.T., Wheaton V.I. & Coughlin, S.R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64, 1057–1068 (1991).
Rasmussen, V.B. et al. cDNA cloning and expression of a hamster α-thrombin receptor coupled to Ca+2 mobilization. FEBS Lett. 288, 123–128 (1991).
Gerszten, R.E. et al. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface. Nature 368, 648–649 (1994).
Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. Molecular cloning of a potential proteinase activated receptor. Proc. Natl. Acad. Sci. USA 91, 9208–9212 (1994).
Nystedt, S., Emilsson, K., Larsson, A.-K., Strombeck, B. & Sundelin, J. Molecular cloning and functional expression of the gene coding for the human proteinase-activated receptor 2. Eur. J. Biochem. 232, 84–89 (1995).
Ishihara, H. et al. Protease-activated receptor-3 is a second thrombin receptor in humans. Nature 386, 502–506 (1997).
Strickland, S. & Richards, W.G. Invasion of trophoblasts. Cell 71, 355–357 (1992).
Cross, J.C., Werb, Z. & Fisher, S.Z. Implantation and the placenta: Key pieces of the development puzzle. Science 266, 1508–1518 (1994).
Damsky, H.C., Fitzgerald, M.L. & Fisher, S.J. Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J. Clin Invest. 89, 210–222 (1992).
Harris, J.R. Placental endogenous retrovitus (ERV): Structural, functional and evolutionary significance. BioEssay 20, 307–316 (1998).
Page, D.L. et al. Atypical hyperplastic lesions of the female breast: a long term follow-up study. Cancer 55, 2698–2708 (1985).
Page, D.L., Steel, C.M. & Dixon, J.M. Carcinoma in situ and patient at high risk of breast cancer. Br. Med. J. 310, 39–42 (1995).
Silverstein, M.J. et al. Duct Carcinoma in situ: 227 cases without micro invasion. Eur. J. Cancer 28, 630–634 (1992).
Fisher, B. et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N. Engl. J. Med. 328, 1581–1586 (1993).
Page, D.L. et al. Continued local recurrence of carcinoma in situ 15–25 years after biopsy only for low grade ductal carcinoma in situ of the breast. Cancer 76, 1197–1200 (1995).
Albini, A. et al. A rapid in vitro assay for quantitating the invasive potential of tumor cells. Cancer Res. 47, 3239–3245 (1987).
Lee, K.S. et al. Sequential activation and production of matrix metalloproteinase-2 during breast cancer progression. Clin. Exp. Metastasis 14, 512–519 (1996).
Kim, S.Y. et al. Sequential production and activation of matrix-metalloproteinase-9 (MMP-9) with breast cancer progression. Breast Cancer Res. Treat. 43, 175–181 (1997).
Walz, D.A. & Fenton II, J.W. The role of thrombin in tumor metastasis. Invasion Metastasis 14, 303–308 (1994).
Nehls, V. & Herrmann, R. The configuration of fibrin clots determines capillary morphogenesis and endothelial cell migration. Microvasc. Res. 51, 347–364 (1996).
Esumi, N., Fan, D. & Fidler, I.J. Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. Cancer Res. 51, 4549–4556 (1991).
Wojtukiewicz, M.Z. et al. Thrombin increases the metastatic potential of tumor cells. Int. J. Cancer 54, 793–806 (1993).
Wojtukiewicz, M.Z. et al. Thrombin enhances tumor cell adhesive and metastatic properties via increased alpha II b beta 3 expression on the cell surface. Thromb. Res. 68, 233–245 (1992).
Wojtukiewicz, M.Z. et al. Solid tumor cells express functional “tethered ligand” thrombin receptor. Cancer Res 55, 698–707 (1995).
Pyke, C.E., Ralkiaer, E., Tryggvson, K. & Dano, K. Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am. J. Pathol 142, 359–365 (1993)
Pyke, C. et al. Messenger RNA for two type IV collagenases is located in stromal cells in human colon cancer. Am. J. Pathol. 138, 1059–1067 (1991).
Sivaraman, V.S., Wang, H.-Y., Nuovo, G.J. & Malbon, C.C. Hyperexpression of Mitogen-activated Protein Kinase in Human Breast Cancer. J. Clin. Invest. 99, 1478–1483 (1977).
Chen, Y.H. et al. She adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin-receptor. EMBO J. 15, 1037–1044 (1996).
Duhamel-Clerin, E. et al. Thrombin receptor-mediated increase of two matrix metalloproteinases, MMP-1 and MMP-3, in human endothelial cells. Arterioscler. Thromb. Vase. Biol. 17, 1931–1938 (1997).
Fernandez, P.L. et al. Immunohistochemical profile of basement membrane proteins and 72 kilodalton type IV collagenase in the implantation placental site. Lab. Invest. 66, 572–579 (1992).
Shimonovitz, S. et al. Developmental regulation of the expression of 72 and 92 kd of type IV collagenases in human trophoblasts: A possible mechanism for control of trophoblast invasion. Am. J. Obstet. Cynecol. 171, 832–838 (1994).
Giancotti, F.G. & Ruoslahti, E. Elevated levels of the α5β1 fibronectin receptor supresses transformed phenotype of Chinese hamster ovary cells. Cell 60, 849–859 (1990).
Soule, H.D. et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res. 50, 6075–6086 (1990).
Miller, F.R. et al. Xenograft model of progressive human proliferative breast disease. J. Natl. Cancer Inst. 85, 1725–1732 (1993).
Feinberg, V. & Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem 132, 6–13 (1984).
Saiki, R.K. et al. Primer-directed enzymatic amplification of DNA with thermostable DNA polymerase. Science 239, 489–491 (1981).
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Even-Ram, S., Uziely, B., Cohen, P. et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 4, 909–914 (1998). https://doi.org/10.1038/nm0898-909
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DOI: https://doi.org/10.1038/nm0898-909
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