Download PDF
Thromb Haemost 2004; 92(01): 185-190
DOI: 10.1160/TH03-11-0679
Cellular Proteolysis and Oncology
Schattauer GmbH

Platelet activation, coagulation and angiogenesis in breast and prostate carcinoma

Graham J. Caine
1   Haemostasis Thrombosis and Vascular Biology Unit, University
,
Gregory Y. H. Lip
1   Haemostasis Thrombosis and Vascular Biology Unit, University
,
Paul S. Stonelake
2   Department of Medicine Department of Surgery, City Hospital, Birmingham, UK
,
Peter Ryan
3   Department of Urology, City Hospital, Birmingham, UK
,
Andrew D. Blann
1   Haemostasis Thrombosis and Vascular Biology Unit, University
› Author Affiliations
Further Information

Publication History

Received 08 November 2003

Accepted after revision 27 April 2004

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

In health, haemostasis and angiogenesis are tightly regulated processes, but may become deregulated in cancer. Recent evidence suggests that platelet activation may link these processes as platelets can release angiogenic factors such as vascular endothelial growth factor (VEGF). Furthermore, inflammation has also been implicated in regulating both coagulation and angiogenesis, possibly by activating platelets directly and increasing, for example, plasma fibrinogen. We hypothesized relationships between plasma markers of the processes in two common forms of cancer. Plasma levels of VEGF (reflecting angiogenesis), soluble P-selectin, (marking platelet activation), tissue factor [TF], fibrinogen and fibrin D-dimer (coagulation markers), and serum levels of IL-6 (inflammation) were measured by ELISA in 30 patients with biopsy-proven breast cancer, 30 patients with biopsy-proven prostate cancer, and 30 ageand sex-matched controls for each group. Prostate specific antigen was also measured in the men. Release of VEGF from IL-6 stimulated platelets was assessed by ELISA. Plasma levels of IL-6 (P <0.02), VEGF, soluble P-selectin, fibrinogen, and fibrin D-dimer (all p <0.01) were significantly raised in breast cancer, whereas VEGF, soluble P-selectin, fibrin D-dimer (all p <0.01) and fibrinogen (p <0.05) were significantly raised in prostate cancer. Significant correlations were found between IL-6 and VEGF (p <0.01), and IL-6 and soluble P-selectin (p = 0.038) in breast cancer. Further experiments demonstrated an in vitro IL-6 induced dose-dependent release of VEGF from platelets. In conclusion, strong relationships between IL6 and VEGF, but not with coagulation or platelet markers, and release of VEGF from IL-6 stimulated platelets, suggest a role for inflammation and platelets in angiogenesis.

Keywords

Angiogenesis - cancer - interleukin-6 - platelets - soluble P-selectin
 

  • References

  • 1 Folkman J. What is the evidence that tumors are angiogenesis dependent?. J Natl Cancer Inst 1990; 82: 4-6.
    CrossrefPubMedGoogle Scholar
  • 2 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86: 353-64.
    CrossrefPubMedGoogle Scholar
  • 3 Griffioen AW, Molema G. Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 2000; 52: 237-68.
    PubMedGoogle Scholar
  • 4 Benjamin L, Golijanin D, Itan A. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999; 103: 159-65.
    CrossrefPubMedGoogle Scholar
  • 5 Dvorak HF, Brown LF, Detmar M. et al. Vascular permeability factor/ vascular endothelial growth factor, microvascular hypermeability, and angiogenesis. Am J Pathol 1995; 146: 1029-39.
    PubMedGoogle Scholar
  • 6 Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000; 55: 15-35.
    PubMedGoogle Scholar
  • 7 Verheul HM, Hoekman K, Luykx-Bakker S. et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 03: 2187-90.
    PubMedGoogle Scholar
  • 8 O’Byrne KJ, Dobbs N, Harris AL. Serum vascular endothelial growth factor load and interleukin-6 in cancer patients. Br J Cancer 2000; 82: 1895-6.
    CrossrefPubMedGoogle Scholar
  • 9 Banks RE, Forbes MA, Kinsey SE. et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998; 77: 956-64.
    CrossrefPubMedGoogle Scholar
  • 10 Bachelot T, Ray-Coquard I, Menetrier-Caux C. et al. Prognostic value of serum levels of interleukin-6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer. Br J Cancer 2003; 88: 1721-6.
    CrossrefPubMedGoogle Scholar
  • 11 Mohle R, Green D, Moore MA. et al. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 1997; 94: 663-8.
    CrossrefPubMedGoogle Scholar
  • 12 Verheul HM, Jorna AS, Hoekman K. et al. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood 2000; 96: 4216-21.
    PubMedGoogle Scholar
  • 13 Blann AD, Lip GYH. Hypothesis: is soluble P selectin a new marker of platelet activation?. Atherosclerosis 1997; 128: 135-8.
    CrossrefPubMedGoogle Scholar
  • 14 Blann AD, Gurney D, Wadley M. et al. Increased soluble P selectin in patients with haematological and breast cancer: a comparison with fibrinogen, plasminogen activator inhibitor and von Willebrand factor. Blood Coag Fibrinolysis 2001; 12: 43-50.
    CrossrefPubMedGoogle Scholar
  • 15 Schadendorf D, Diehl S, Zuberbier T. et al. Quantitative detection of soluble adhesion molecules in sera of melanoma patients correlates with clinical stage. Dermatology 1996; 192: 89-93.
    CrossrefPubMedGoogle Scholar
  • 16 Haznedaroglou IC, Benekli M, Ozcebe O. et al. Serum L-selectin and P-selectin levels in lymphomas. Haematologica 2000; 30: 27-30.
    PubMedGoogle Scholar
  • 17 Roselli M, Mineo TC, Basili S. et al. Vascular endothelial growth factor (VEGF-A) plasma levels in non-small cell lung cancer: relationship with coagulation and platelet activation markers. Thromb Haemost 2003; 89: 177-84.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Roselli M, Mineo TC, Martini F. et al. Serum concentrations of soluble selectins in patients with lung cancer. Int J Biol Markers 2002; 17: 56-62.
    CrossrefPubMedGoogle Scholar
  • 19 Salgado R, Benoy I, Weytjens R. et al. Arteriovenous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer. Br J Cancer 2002; 87: 1437-44.
    CrossrefPubMedGoogle Scholar
  • 20 Nakashima J, Tachibana M, Horiguchi Y. et al. Serum interleukin-6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000; 06: 2702-6.
    PubMedGoogle Scholar
  • 21 Bachelot T, Ray-Coquard I, Menetrier-Caux C. et al. Prognostic value of serum levels of interleukin-6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer. Br J Cancer 2003; 88: 1721-6.
    CrossrefPubMedGoogle Scholar
  • 22 Osterud B. Tissue factor: a complex biological role. Thromb Haemost 1997; 78: 755-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Bromberg ME, Sundaram R, Homer RJ. et al. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. Thromb Haemost 1999; 82: 88-92.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Folkman J. Tumor angiogenesis and tissue factor. Nat Med 1996; 167-8.
    PubMedGoogle Scholar
  • 25 Kakkar AK, DeRuvo N, Chinswangwatanakul V. et al. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-5.
    CrossrefPubMedGoogle Scholar
  • 26 Ueno T, Toi M, Koike M. et al. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration. Br J Cancer 2000; 83: 164-70.
    CrossrefPubMedGoogle Scholar
  • 27 Makin AJ, Chung NA, Silverman SH. et al. Vascular endothelial growth factor and tissue factor in patients with established peripheral vascular disease: a link between angiogenesis and thrombogenesis?. Clin Sci 2003; 104: 397-404.
    CrossrefPubMedGoogle Scholar
  • 28 Kamath S, Blann AD, Caine GJ. et al. Platelet P selectin in relation to plasma soluble P selectin and beta-thromboglobulin levels in atrial fibrillation. Stroke 2002; 33: 1237-42.
    CrossrefPubMedGoogle Scholar
  • 29 Roldan V, Marin F, Blann AD. et al. Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation. Eur Heart J 2003; 24: 1373-80.
    CrossrefPubMedGoogle Scholar
  • 30 Belgore FM, Lip GYH, Wadley M. et al. Plasma levels of vascular endothelial cell growth factor (VEGF) and its receptor (sFlt-1) in haematological cancers: a comparison with breast cancer. Am J Haematol 2001; 66: 59-61.
    CrossrefPubMedGoogle Scholar
  • 31 Altman D. Practical statistics for Medical Research. Chapman Hall; London: 1991
    Google Scholar
  • 32 Bachelot T, Ray-Coquard I, Menetrier-Caux C. et al. Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of VEGF in hormone-refractory metastatic breast cancer patients. Br J Cancer 2003; 88: 1721-6.
    CrossrefPubMedGoogle Scholar
  • 33 Ferrari L, Bajetta E, Martinetti A. et al. Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole?. Int J Oncol 2003; 22: 1081-9.
    PubMedGoogle Scholar
  • 34 Salgado R, Junius S, Benoy I. et al. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 2003; 103: 642-6.
    CrossrefPubMedGoogle Scholar
  • 35 Benoy I, Salgado R, Colpaert C. et al. Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. Clin Breast Cancer 2002; 02: 311-5.
    CrossrefPubMedGoogle Scholar
  • 36 Pfitzenmaier J, Vessella R, Higano CS. et al. Elevation of cytokine levels in cachectic patients with prostate carcinoma. Cancer 2003; 97: 1211-6.
    CrossrefPubMedGoogle Scholar
  • 37 Akakura K, Suzuki H, Ueda T. et al. Possible mechanism of dexamethasone therapy for prostate cancer: suppression of circulating level of interleukin-6. Prostate 2003; 56: 106-9.
    CrossrefPubMedGoogle Scholar
  • 38 Nakashima J, Tachibana M, Horiguchi Y. et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000; 06: 2702-6.
    PubMedGoogle Scholar
  • 39 Wise GJ, Marella VK, Talluri G. et al. Cytokine variations in patients with hormone treated prostate cancer. J Urol 2000; 164: 722-5.
    CrossrefPubMedGoogle Scholar
  • 40 Salgado R, Vermeulen PB, Benoy I. et al. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels in advanced cancer. Br J Cancer 1999; 80: 892-7.
    CrossrefPubMedGoogle Scholar
  • 41 Vermeulen PB, Salven P, Benoy I. et al. Blood platelets and serum VEGF in cancer patients. Br J Cancer 1999; 79: 370-3.
    CrossrefPubMedGoogle Scholar
  • 42 Caine GJ, Stonelake PS, Lip GY. et al. The hypercoagulable state of malignancy; pathogenesis and current debate. Neoplasia 2002; 04: 465-73.
    CrossrefPubMedGoogle Scholar
  • 43 Lip GYH, Chin BSP, Blann AD. Cancer and the prothrombotic state. Lancet Oncology 2002; 03: 27-34.
    CrossrefPubMedGoogle Scholar
  • 44 Blay JY, Rossi JF, Wijdenes J. et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer 1997; 72: 424-30.
    CrossrefPubMedGoogle Scholar
  • 45 Salgado R, Benoy I, Bogers J. et al. Platelets and vascular endothelial growth factor (VEGF): a morphological and functional study. Angiogenesis 2001; 04: 37-43.
    CrossrefPubMedGoogle Scholar
  • 46 Caine GJ, Lip GYH, Blann AD. Plateletderived VEGF, flt-1, angiopoietin-1 and Pselectin in breast and prostate cancer: further evidence for a role of platelets in tumour angiogenesis. Annals Med. 2004 In press.
    PubMedGoogle Scholar
  • 47 Blann AD, Nadar SK, Lip GYH. The adhesion molecule P-selectin and cardiovascular disease. Eur Heart J 2003; 24: 2166-79.
    CrossrefPubMedGoogle Scholar