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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2746-2751. Prepublished online as a Blood First Edition Paper on July 20, 2004; DOI 10.1182/blood-2004-03-1047. This Article Full Text (PDF) All Versions of this Article: 2004-03-1047v1 104/9/2746    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hu, L. Articles by Karpatkin, S. Search for Related Content PubMed PubMed Citation Articles by Hu, L. Articles by Karpatkin, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 19, 2004 Accepted June 2, 2004 Role of Endogenous Thrombin in Tumor Implantation, Seeding and Spontaneous Metastasis Liang Hu, Merlin Lee, Wendy Campbell, Roman Perez-Solar, and Simon Karpatkin* Department of Medicine, New York University School of Medicine, New York, NY, USA * Corresponding author; email: simon.karpatkin{at}med.nyu.edu. Tumor/host generated thrombin (endogenous thrombin) was investigated with tumor growth and metastasis experiments in mice by the use of hirudin, a highly potent specific inhibitor of thrombin. Pretreatment with hirudin inhibited tumor implantation in nude or syngeneic mice, following subcutaneous injection of two human and two murine tumors. Hirudin induced a considerable lag period in the appearance of tumor growth, compared to PBS treatment, but had no effect on established tumor nodule growth in vivo or on tumor growth in vitro. Hirudin tretment induced central necrosis of the tumor nodule compared to no effect with PBS treatment. Greater protection was noted with longer duration of treatment. Tumor seeding into blood was examined with GFP-labeled tumor cells. Hirudin inhibited seeding into the blood as well as systemic organs which varied from complete protection to 15-32 fold in the blood and 17-395 fold in the lung. Hirudin inhibited spontaneous metastases from subcutaneously implanted tumor by reducing the number of tumor nodules in the lungs. Mouse survival in animals injected subcutaneously with highly aggressive 4T1 cells revealed 5 of 5 deaths of PBS-treated animals on day 40 compared to no deaths with hirudin treatment-with prolongation of survival with hirudin treatment of 16 to >31 days. Thus endogenous thrombin contributes to tumor implantation, seeding and spontaneous metastasis. A potent anti-thrombin agent should be of clinical benefit to patients with cancer. 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