Thromb Haemost 2003; 89(01): 185-189
DOI: 10.1055/s-0037-1613558
Cellular Proteolysis and Oncology
Schattauer GmbH

Correlates of thrombin generation in patients with advanced prostate cancer

Stuart E. Lind
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
,
Joseph A. Caprini
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
,
Sofia Goldshteyn
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
,
James C. Dohnal
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
,
Sara K. Vesely
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
,
Daniel H. Shevrin
1   The Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and the Departments of Medicine, Pathology and Surgery, Evanston Northwestern Healthcare and Northwestern University Medical School, Evanston, Illinois, USA
› Author Affiliations
Further Information

Publication History

Received 06 September 2002

Accepted after revision 01 November 2002

Publication Date:
09 December 2017 (online)

Summary

Thrombin generation is increased in men with advanced prostate cancer. Thrombin has the ability to interact with, and affect the biology of, a variety of cell types including prostate cancer cell lines. We therefore looked for correlations between thrombin generation and other markers of disease activity in spot urine samples obtained from men with advanced prostate cancer. Excretion of part of the prothrombin activation peptide F1+2 (called here iF2), interleukin-6 (IL-6), the bone turnover marker deoxypyridinoline (DpD), and vascular endothelial growth factor (VEGF) were quantitated in spot urine samples collected from 37 men with hormone-refractory prostate cancer. Following log transformation of the data, significant correlations were found by univariate analysis between the excretion of a marker of thrombin generation (iF2) and IL-6, DpD and VEGF, as well as between IL-6 and DpD or VEGF excretion. No correlation was found between any marker and serum PSA level. After multivariate analysis, a significant correlation remained between thrombin generation and IL-6 excretion. Analysis of a second urine specimen obtained from 19 of the subjects 1 to 7 months after the first also revealed a significant correlation between thrombin generation and IL-6, DpD, and VEGF excretion. These data provide evidence of a correlation between thrombin generation/coagulation system activation and IL-6 generation in patients with cancer. They provide a rationale for studying the effects of inhibitors of thrombin generation upon the biology of prostate cancer.

 
  • References

  • 1 Rickles FR, Edwards RL. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14.
  • 2 Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci USA 1999; 96: 11023.
  • 3 Yoshida E, Verrusio EN, Mihara H. et al. Enhancement of the expression of urokinase-type plasminogen activator from PC-3 human prostate cancer cells by thrombin. Cancer Res 1994; 54: 3300.
  • 4 Zain J, Huang YQ, Feng X. et al. Concentration-dependent dual effect of thrombin on impaired growth/apoptosis or mitogenesis in tumor cells. Blood 2000; 95: 3133.
  • 5 Nierodzik ML, Chen K, Takeshita K. et al. Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis. Blood 1998; 92: 3694.
  • 6 Henrikson KP, Salazar SL, Fenton JW. 2nd et al. Role of thrombin receptor in breast cancer invasiveness. Br J Cancer 1999; 79: 401.
  • 7 Lind SE, Goldshteyn S, Barry CP. et al. Assessment of coagulation system activation using spot urine measurements. Blood Coagul Fibrinolysis 1999; 10: 285.
  • 8 Nakashima J, Tachibana M, Horiguchi Y. et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000; 6: 2702.
  • 9 Okamoto M, Lee C, Oyasu R. Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. Cancer Res 1997; 57: 141.
  • 10 Smith PC, Hobisch A, Lin D. et al. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev 2001; 12: 33.
  • 11 Cushman M, Psaty BM, Macy E. et al. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterioscler Thromb Vasc Biol 1996; 16: 1163.
  • 12 Papatheofanis FJ. Quantitation of biochemical markers of bone resorption following strontium-89-chloride therapy for metastatic prostatic carcinoma. J Nucl Med 1997; 38: 1175.
  • 13 Gustafson GT, Lerner U. Thrombin, a stimulator of bone resorption. Biosci Rep 1983; 3: 255.
  • 14 Tatakis DN, Dolce C, Dziak R. Thrombin’s effects on osteoblastic cells. I. Cytosolic calcium and phosphoinositides. Biochem Biophys Res Commun 1989; 164: 119.
  • 15 Kozawa O, Tokuda H, Kaida T. et al. Thrombin regulates interleukin-6 synthesis through phosphatidylcholine hydrolysis by phospholipase D in osteoblasts. Arch Biochem Biophys 1997; 345: 10.
  • 16 Saaristo A, Karpanen T, Alitalo K.. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene 2000; 19: 6122.
  • 17 Strohmeyer D, Rossing C, Bauerfeind A. et al. Vascular endothelial growth factor and its correlation with angiogenesis and p53 expression in prostate cancer. Prostate 2000; 45: 216.
  • 18 Bok RA, Halabi S, Fei DT. et al. Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study. Cancer Res 2001; 61: 2533.
  • 19 Tsopanoglou NE, Maragoudakis ME. On the mechanism of thrombin-induced angio-genesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up- regulation of its receptors. J Biol Chem 1999; 274: 23969.
  • 20 Dankbar B, Padro T, Leo R. et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630.