Effect of anti-fibrinolytic therapy on experimental melanoma metastasis

Abstract

Anti-fibrinolytic agents such as aprotinin and epsilon-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.

Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

“…Surgery commenced 10 minutes following tumor inoculation. Animals were euthanized at 18 hours or 3 days following tumor inoculation, and their lungs were stained with X-gal (Bioshop) as described previously (30). Total number of surface visible metastases was determined on the largest lung lobe (left lobe) using a stereomicroscope (Leica Microsystems).…”

“…Evaluation of the role of NK cells in postoperative tumor metastases NK cells were depleted using a-asialoGM1 antibody (Cedarlane) as previously described (30). The lung tumor burden was quantified at 3 days postsurgery…”

Ly49 Family Receptors Are Required for Cancer Immunosurveillance Mediated by Natural Killer Cells

“…Animals were euthanized 5 or 14 days following tumor inoculation and lungs were stained with X-gal (Bioshop) as described previously (22). Representative tumor burden was determined on the largest lung (left) lobe, by the number of surface visible metastases.…”

Clinical and prognostic significance of coagulation assays in melanoma

“…High levels of circulating biomarkers resembling activated coagulation and fibrinolytic systems such as fibrinogen (F), fibrin(ogen) split products and DD have been associated with decreased survival for several tumor types in previous studies [11][12][13]. Researches on melanoma patients examining the relationship between activated hemostatic system and prognosis have yielded similar results [14][15][16]. Sufficient evidence of such an advantage has not been found for cancer patients in general.…”