Abstract
BackgroundPatients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model.MethodsMetastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system.ResultsWild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner.ConclusionPlasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain.
Highlights
Patients with metastatic tumors to the brain have a very poor prognosis
Cell culture B16F10 mouse melanoma cells and SK-melanoma cells (SK-Mel) human melanoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) and 10% fetal calf serum (FCS)
Fate of intracarotid injected mouse melanoma cells To determine the fate of the injected cells we labeled B16F10 cells with 125I-deoxyuridine. 125I-deoxyuridine is incorporated in the DNA of the B16F10 cells and is not taken up by other mouse cells after injection [16]
Summary
Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. CNS metastases are an important cause of disease relapse following high-dose chemotherapy with bone marrow or stem cell support [7] and a common reason for exclusion of patients from highdose chemotherapy protocols because of poor penetration of drugs into the CNS. For these reasons, strategies for preventing CNS metastases and growth from systemic cancer are vitally important
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