HOST PLASMINOGEN ACTIVATOR INHIBITOR-1 PLAYS A DETERMINANT ROLE IN
TUMOR PROGRESSION AND ANGIOGENESIS: PROPOSAL OF AN ANTITUMOR THERAPY
TARGETING THE HOST-DERIVED FACTOR
Department of Molecular and Internal Medicine, Graduate School of Biomedical & Health Sciences,
Hiroshima University, Japan
Plasminogen activator inhibitor-1 (PAI-1) is intimately involved in tumor progression. In the tumor microenvironment, PAI-1 can be produced by host and tumor cells. However, it has not been fully elucidated whether host or tumor-derived PAI-1 is more crucial to tumor progression. To compare the relevance of host and tumor PAI-1 in tumor progression, subcutaneous tumor and tail vein metastasis models were established in PAI-1-deficient and wild-type mice using Lewis lung carcinoma (LLC) and PAI-1 knockdown LLC cells. Sizes of subcutaneous tumors and the extent of metastases were shown to be controlled by the presence of host PAI-1 and not affected by the PAI-1 levels in the tumors. Similarly, host PAI-1 played a more crucial role in tumor angiogenesis than did tumor PAI-1. To pursue the possibility that host PAI-1 could be a therapeutic target, SK-216, a specific PAI-1 inhibitor, was orally administered to mice subcutaneously implanted or intravenously injected with LLC cells. The systemic administration of SK-216 reduced the sizes of subcutaneous tumors and the extent of metastases. Similar results were obtained even when PAI-1 non-secreting B16 melanoma cells were used in these models. SK-216 also reduced the extent of angiogenesis in the tumors and inhibited VEGF-induced migration and tube formation of human umbilical vein endothelial cells. These observations suggest that host PAI-1 plays a determinant role in tumor progression through its effects on tumor angiogenesis. The systemic administration of SK-216 targeting host PAI-1 could be a therapeutic option in the treatment of malignancy.