Clinical & Experimental Metastasis

, Volume 26, Issue 2, pp 121–131

Effect of anti-fibrinolytic therapy on experimental melanoma metastasis

  • Jennifer M. Kirstein
  • Kevin C. Graham
  • Lisa T. MacKenzie
  • Danielle E. Johnston
  • Leslie J. Martin
  • Alan B. Tuck
  • Ian C. MacDonald
  • Ann F. Chambers
Research Paper

DOI: 10.1007/s10585-008-9221-z

Cite this article as:
Kirstein, J.M., Graham, K.C., MacKenzie, L.T. et al. Clin Exp Metastasis (2009) 26: 121. doi:10.1007/s10585-008-9221-z

Abstract

Anti-fibrinolytic agents such as aprotinin and ε-aminocaproic acid (EACA) are used clinically to decrease peri-operative bleeding. Use of these treatments during cancer-related surgeries has led to investigation of the effect of fibrinolysis inhibition on cancer cell spread. The ability of aprotinin to reduce proteolytic activity of proteases required for metastasis suggests that it could have an anti-metastatic effect in patients undergoing tumor resection. However, many metastatic cells in the vasculature of a secondary tissue are associated with a micro-thrombus. The association of tumor cells with thrombi has been shown to increase their survival; therefore inhibition of plasmin-mediated fibrinolysis might instead increase metastatic cell survival by enhancing the association between thrombi and tumor cells. The goal of this work was to determine the effect of anti-fibrinolytic treatment on experimental metastasis and to establish the role of coagulation factors in this effect. The metastatic ability of B16F10 melanoma cells was evaluated in vivo following cell or animal pre-treatment with aprotinin or EACA. Additionally, a novel in vivo technique was developed, to permit analysis of tumor cell association with thrombi in the lung microvasculature using confocal microscopy. Aprotinin and EACA treatment of mice resulted in a significant increase in lung metastasis. Aprotinin treatment increased the size of thrombi in association with cells arrested in lung capillaries. This study suggests that clinical use of anti-fibrinolytic agents for cancer-related surgeries could result in increased metastatic ability of those cells shed immediately prior to and during surgery, and that this approach thus requires further study.

Keywords

Anti-fibrinolyticAprotininEACAMetastasisCoagulation

Abbreviations

EACA

ε-Aminocaproic acid

TXA

Tranexamic acid

MMP

Matrix metalloproteinase

ECM

Extracellular matrix

CMFDA

5-Chloromethylfluorescein diacetate

H&E

Hematoxylin and eosin

TF

Tissue factor

CP

Cancer procoagulant

LLC

Lewis lung carcinoma

NK

Natural killer immune cells

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Jennifer M. Kirstein
    • 1
    • 2
  • Kevin C. Graham
    • 1
    • 2
  • Lisa T. MacKenzie
    • 2
  • Danielle E. Johnston
    • 2
  • Leslie J. Martin
    • 2
  • Alan B. Tuck
    • 1
    • 3
    • 4
  • Ian C. MacDonald
    • 2
    • 4
  • Ann F. Chambers
    • 1
    • 2
    • 3
    • 4
  1. 1.London Regional Cancer ProgramLondon Health Sciences CentreLondonCanada
  2. 2.Department of Medical BiophysicsUniversity of Western OntarioLondonCanada
  3. 3.Department of PathologyUniversity of Western OntarioLondonCanada
  4. 4.Department of OncologyUniversity of Western OntarioLondonCanada