Prothrombotic Effects of Prostasomes Isolated from Prostatic Cancer Cell Lines and Seminal Plasma

ABSTRACT

Thromboembolism is well recognized as a major complication of cancer. Many tumor cells overexpress tissue factor (TF), which activates blood coagulation in cancer patients. Inflammatory cells expressing TF are also contributors to this activation. In prostate cancer, we believe that prostasomes may also be involved in the initiation of blood coagulation. Prostasomes are submicron secretory granules derived from the prostate gland. They are surrounded by membrane and their extracellular appearance and membrane architecture are complex. Seminal prostasomes are believed to be necessary for successful fertilization and act as protectors of the spermatozoa in the lower and upper female genital tract. Cells from prostate cancer and its metastases are able to produce and export prostasomes to the extracellular environment. These prostasomes may differ quantitatively rather than qualitatively from their normal counterparts with regard to protein composition and function. A majority of human prostate cancers have been found to overexpress TF, and we have demonstrated by various methods that prostasomes derived from prostate cancer cells express considerably higher levels of TF compared with prostasomes of nonmalignant cell origin. The mechanism related to thromboembolic disease generated by prostasomes in prostatic cancer patients may be the early release of prostasomes from prostate cancer cells into the blood circulation, where they will evoke their blood-clotting effects.

KEYWORDS

Thromboembolism - tissue factor - blood coagulation - prostasomes - prostate cancer

REFERENCES

• 1 Donati M B. Cancer and thrombosis: from Phlegmasia alba dolens to transgenic mice.  Thromb Haemost. 1995;  74 278-281
• 2 Francis J L, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy.  Semin Thromb Hemost. 1998;  24 93-109
• 3 Arkel Y S. Thrombosis and cancer.  Semin Oncol. 2000;  27 362-374
• 4 Rickles F R, Falanga A. Molecular basis for the relationship between thrombosis and cancer.  Thromb Res. 2001;  102 V215-V224
• 5 Rickles F R, Patierno S, Fernandez P M. Tissue factor, thrombin, and cancer.  Chest. 2003;  124 58S-68S
• 6 Furie B, Furie B C. Thrombus formation in vivo.  J Clin Invest. 2005;  115 3355-3362
• 7 Oefelein M G, Brant M, Crotty K. Idiopathic thromboembolism as the presenting sign of occult prostate cancer.  Urology. 1998;  51 775-780
• 8 Dvorak H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.  N Engl J Med. 1986;  315 1650-1659
• 9 Dvorak H F, Nagy J A, Berse B et al.. Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation.  Ann NY Acad Sci. 1992;  667 101-111
• 10 Edwards R L, Silver J, Rickles F R. Human tumor procoagulants: registry of the Subcommittee on Haemostasis and Malignancy of the Scientific and Standardization Committee, International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1993;  69 205-213
• 11 Sawada M, Miyake S, Ohdama S et al.. Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis.  Br J Cancer. 1999;  79 472-477
• 12 Costantini V, De Monte P, Cazzato A O et al.. Systemic thrombin generation in cancer patients is correlated with extrinsic pathway activation.  Blood Coagul Fibrinolysis. 1998;  9 79-84
• 13 Broze G JJ. Binding of human factor VII and VIIa to monocytes.  J Clin Invest. 1982;  70 526-535
• 14 Ronquist G, Brody I. The prostasome: its secretion and function in man.  Biochim Biophys Acta. 1985;  822 203-218
• 15 Ronquist G, Brody I, Gottfries A, Stegmayr B. An Mg2 + and Ca2 + -stimulated adenosine triphosphatase in human prostatic fluid: part I.  Andrologia. 1978;  10 261-272
• 16 Ronquist G, Brody I, Gottfries A, Stegmayr B. An Mg2 + and Ca2 + -stimulated adenosine triphosphatase in human prostatic fluid-part II.  Andrologia. 1978;  10 427-433
• 17 Nilsson B O, Jin M, Einarsson B, Persson B E, Ronquist G. Monoclonal antibodies against human prostasomes.  Prostate. 1998;  35 178-184
• 18 Stoorvogel W, Kleijmeer M J, Geuze H J, Raposo G. The biogenesis and functions of exosomes.  Traffic. 2002;  3 321-330
• 19 Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function.  Nat Rev Immunol. 2002;  2 569-579
• 20 Johnstone R M. Exosomes biological significance: a concise review.  Blood Cells Mol Dis. 2006;  36 315-321
• 21 Stegmayr B, Brody I, Ronquist G. A biochemical and ultrastructural study on the endogenous protein kinase activity of secretory granule membranes of prostatic origin in human seminal plasma.  J Ultrastruct Res. 1982;  78 206-214
• 22 Sahlen G E, Egevad L, Ahlander A, Norlen B J, Ronquist G, Nilsson B O. Ultrastructure of the secretion of prostasomes from benign and malignant epithelial cells in the prostate.  Prostate. 2002;  53 192-199
• 23 Arienti G, Carlini E, Saccardi C, Palmerini C A. Role of human prostasomes in the activation of spermatozoa.  J Cell Mol Med. 2004;  8 77-84
• 24 Ronquist G, Nilsson B O, Hjerten S. Interaction between prostasomes and spermatozoa from human semen.  Arch Androl. 1990;  24 147-157
• 25 Stegmayr B, Ronquist G. Promotive effect on human sperm progressive motility by prostasomes.  Urol Res. 1982;  10 253-257
• 26 Fabiani R, Johansson L, Lundkvist Ö, Ronquist G. Enhanced recruitment of motile spermatozoa by prostasome inclusion in swim-up medium.  Hum Reprod. 1994;  9 1485-1489
• 27 Arienti G, Carlini E, Nicolucci A, Cosmi E V, Santi F, Palmerini C A. The motility of human spermatozoa as influenced by prostasomes at various pH levels.  Biol Cell. 1999;  91 51-54
• 28 Cross N L. Effect of cholesterol and other sterols on human sperm acrosomal responsiveness.  Mol Reprod Dev. 1996;  45 212-217
• 29 Cross N L, Mahasreshti P. Prostasome fraction of human seminal plasma prevents sperm from becoming acrosomally responsive to the agonist progesterone.  Arch Androl. 1997;  39 39-44
• 30 Minelli A, Allegrucci C, Liguori L, Ronquist G. Ecto-diadenosine polyphosphates hydrolase activity on human prostasomes.  Prostate. 2002;  51 1-9
• 31 Breitbart H, Cohen G, Rubinstein S. Role of actin cytoskeleton in mammalian sperm capacitation and the acrosome reaction.  Reproduction. 2005;  129 263-268
• 32 Skibinski G, Kelly R W, Harkiss D, James K. Immunosuppression by human seminal plasma-extracellular organelles (prostasomes) modulate activity of phagocytic cells.  Am J Reprod Immunol. 1992;  28 97-103
• 33 Kelly R W. Immunosuppressive mechanisms in semen: implications for contraception.  Hum Reprod. 1995;  10 1686-1693
• 34 Kelly R W, Holland P, Skibinski G et al.. Extracellular organelles (prostasomes) are immunosuppressive components of human semen.  Clin Exp Immunol. 1991;  86 550-556
• 35 Iwasaki A, Gagnon C. Formation of reactive oxygen species in spermatozoa of infertile patients.  Fertil Steril. 1992;  57 409-416
• 36 Saez F, Motta C, Boucher D, Grizard G. Antioxidant capacity of prostasomes in human semen.  Mol Hum Reprod. 1998;  4 667-672
• 37 Carlsson L, Pahlson C, Bergquist M, Ronquist G, Stridsberg M. Antibacterial activity of human prostasomes.  Prostate. 2000;  44 279-286
• 38 Carlsson L, Nilsson O, Larsson A, Stridsberg M, Sahlen G, Ronquist G. Characteristics of human prostasomes isolated from three different sources.  Prostate. 2003;  54 322-330
• 39 Nilsson B O, Lennartsson L, Carlsson L, Nilsson S, Ronquist G. Expression of prostasome-like granules by the prostate cancer cell lines PC3, Du145 and LnCaP grown in monolayer.  Ups J Med Sci. 1999;  104 199-206
• 40 Wang J, Lundqvist M, Carlsson L, Nilsson O, Lundkvist O, Ronquist G. Prostasome-like granules from the PC-3 prostate cancer cell line increase the motility of washed human spermatozoa and adhere to the sperm.  Eur J Obstet Gynecol Reprod Biol. 2001;  96 88-97
• 41 Floryk D, Tollaksen S L, Giometti C S, Huberman E. Differentiation of human prostate cancer PC-3 cells induced by inhibitors of inosine 5′-monophosphate dehydrogenase.  Cancer Res. 2004;  64 9049-9056
• 42 Llorente A, de Marco M C, Alonso M A. Caveolin-1 and MAL are located on prostasomes secreted by the prostate cancer PC-3 cell line.  J Cell Sci. 2004;  117 5343-5351
• 43 Arvidson G, Ronquist G, Wikander G, Ojteg A C. Human prostasome membranes exhibit very high cholesterol/phospholipid ratios yielding high molecular ordering.  Biochim Biophys Acta. 1989;  984 167-173
• 44 Utleg A G, Yi E C, Xie T et al.. Proteomic analysis of human prostasomes.  Prostate. 2003;  56 150-161
• 45 Fernandez J A, Heeb M J, Radtke K P, Griffin J H. Potent blood coagulant activity of human semen due to prostasome-bound tissue factor.  Biol Reprod. 1997;  56 757-763
• 46 Hegmans J P, Bard M P, Hemmes A et al.. Proteomic analysis of exosomes secreted by human mesothelioma cells.  Am J Pathol. 2004;  164 1807-1815
• 47 Wolfers J, Lozier A, Raposo G et al.. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.  Nat Med. 2001;  7 297-303
• 48 Andre F, Andersen M, Wolfers J et al.. Exosomes in cancer immunotherapy: preclinical data.  Adv Exp Med Biol. 2001;  495 349-354
• 49 Fabiani R, Ronquist G. Association of some hydrolytic enzymes with the prostasome membrane and their differential responses to detergent and PIPLC treatment.  Prostate. 1995;  27 95-101
• 50 Rooney I A, Atkinson J P, Krul E S et al.. Physiologic relevance of the membrane attack complex inhibitory protein CD59 in human seminal plasma: CD59 is present on extracellular organelles (prostasomes), binds cell membranes, and inhibits complement-mediated lysis.  J Exp Med. 1993;  177 1409-1420
• 51 Babiker A A, Ronquist G, Nilsson U R, Nilsson B. Transfer of prostasomal CD59 to CD59-deficient red blood cells results in protection against complement-mediated hemolysis.  Am J Reprod Immunol. 2002;  47 183-192
• 52 Babiker A A, Nilsson B, Ronquist G, Carlsson L, Ekdahl K N. Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attack.  Prostate. 2005;  62 105-114
• 53 Camerer E, Kolsto A B, Prydz H. Cell biology of tissue factor, the principal initiator of blood coagulation.  Thromb Res. 1996;  81 1-41
• 54 Ruf W, Edgington T S. Structural biology of tissue factor, the initiator of thrombogenesis in vivo.  FASEB J. 1994;  8 385-390
• 55 Fan Z, Larson P J, Bognacki J et al.. Tissue factor regulates plasminogen binding and activation.  Blood. 1998;  91 1987-1998
• 56 de Vries T J, van Muijen G N, Ruiter D J. The plasminogen activation system in tumour invasion and metastasis.  Pathol Res Pract. 1996;  192 718-733
• 57 Preissner K T, Seiffert D. Role of vitronectin and its receptors in haemostasis and vascular remodeling.  Thromb Res. 1998;  89 1-21
• 58 Bronson R A, Preissner K T. Measurement of vitronectin content of human spermatozoa and vitronectin concentration within seminal fluid.  Fertil Steril. 1997;  68 709-713
• 59 Van Dreden P, Gonzales J, Poirot C. Human seminal fibrinolytic activity: specific determinations of tissue plasminogen activator and urokinase.  Andrologia. 1991;  23 29-33
• 60 Schvartz I, Seger D, Shaltiel S. Vitronectin.  Int J Biochem Cell Biol. 1999;  31 539-544
• 61 Schvartz I, Kreizman T, Brumfeld V, Gechtman Z, Seger D, Shaltiel S. The PKA phosphorylation of vitronectin: effect on conformation and function.  Arch Biochem Biophys. 2002;  397 246-252
• 62 Babiker A A, Nilsson B, Ronquist G, Ekdahl K N. Overexpression of ecto-protein kinases in prostasomes of metastatic origin.  Prostate. 2006;  66 675-686
• 63 Forsberg P O, Martin S C. Phosphorylation/dephosphorylation and the regulation of fibrinogen and complement factor C3.  Ups J Med Sci. 1991;  96 75-93
• 64 Lwaleed B A, Greenfield R, Stewart A, Birch B, Cooper A J. Seminal clotting and fibrinolytic balance: a possible physiological role in the male reproductive system.  Thromb Haemost. 2004;  92 752-766
• 65 Lwaleed B A, Greenfield R S, Birch B R, Cooper A J. Does human semen contain a functional haemostatic system? A possible role for tissue factor pathway inhibitor in fertility through semen liquefaction.  Thromb Haemost. 2005;  93 847-852
• 66 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2 + signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem. 1995;  270 4650-4660
• 67 Weidner N, Carroll P R, Flax J, Blumenfeld W, Folkman J. Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.  Am J Pathol. 1993;  143 401-409
• 68 Lissbrant I F, Stattin P, Damber J E, Bergh A. Vascular density is a predictor of cancer-specific survival in prostatic carcinoma.  Prostate. 1997;  33 38-45
• 69 Abdulkadir S A, Carvalhal G F, Kaleem Z et al.. Tissue factor expression and angiogenesis in human prostate carcinoma.  Hum Pathol. 2000;  31 443-447
• 70 Babiker A A, Hamad O A, Sanchez J, Ronquist G, Nilsson B, Ekdahl K N. Prothrombotic effect of prostasomes of metastatic cell and seminal origin.  Prostate. 2007;  , In press
• 71 Zioncheck T F, Roy S, Vehar G A. The cytoplasmic domain of tissue factor is phosphorylated by a protein kinase C-dependent mechanism.  J Biol Chem. 1992;  267 3561-3564
• 72 Mody R S, Carson S D. Tissue factor cytoplasmic domain peptide is multiply phosphorylated in vitro.  Biochemistry. 1997;  36 7869-7875
• 73 Sahlen G, Ahlander A, Frost A, Ronquist G, Norlen B J, Nilsson B O. Prostasomes are secreted from poorly differentiated cells of prostate cancer metastases.  Prostate. 2004;  61 291-297
• 74 Hara N, Kasahara T, Kawasaki T et al.. Frequency of PSA-mRNA-bearing cells in the peripheral blood of patients after prostate biopsy.  Br J Cancer. 2001;  85 557-562
• 75 Schleiermacher G, Delattre O. Detection of micrometastases and circulating tumour cells using molecular biology technics in solid tumours.  Bull Cancer. 2001;  88 561-570
• 76 Siddall J K, Shetty S D, Cooper E H. Measurements of serum gamma-seminoprotein and prostate specific antigen evaluated for monitoring carcinoma of the prostate.  Clin Chem. 1986;  32 2040-2043