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Human pancreatic tumors grown in mice release tissue factor‐positive microvesicles that increase venous clot size
Author(s) -
Hisada Y.,
Ay C.,
Auriemma A. C.,
Cooley B. C.,
Mackman N.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13809
Subject(s) - tissue factor , medicine , pancreatic cancer , thrombosis , pathology , microvesicles , cancer , histopathology , cancer research , coagulation , biology , microrna , gene , biochemistry
Essentials Tumor‐bearing mice have larger venous clots than controls. Human tissue factor is present in clots in tumor‐bearing mice. Inhibition of human tissue factor reduces clot size in tumor‐bearing mice. This new mouse model may be useful to study mechanisms of cancer‐associated thrombosis.Summary Background Pancreatic cancer patients have a high rate of venous thromboembolism. Human pancreatic tumors and cell lines express high levels of tissue factor ( TF ), and release TF ‐positive microvesicles ( TF + MV s). In pancreatic cancer patients, tumor‐derived TF + MV s are present in the blood, and increased levels are associated with venous thromboembolism and decreased survival. Previous studies have shown that mice with orthotopic human or murine pancreatic tumors have circulating tumor‐derived TF + MV s, an activated clotting system, and increased incidence and mean clot weight in an inferior vena cava stenosis model. These results suggest that TF + MV s contribute to thrombosis. However, the specific role of tumor‐derived TF + MV s in venous thrombosis in mice has not been determined. Objectives To test the hypothesis that tumor‐derived TF + MV s enhance thrombosis in mice. Methods We determined the contribution of TF + MV s derived from human pancreatic tumors grown orthotopically in nude mice to venous clot formation by using an anti‐human TF mAb. We used an inferior vena cava stasis model of venous thrombosis. Results Tumor‐bearing mice had significantly larger clots than control mice. Clots from tumor‐bearing mice contained human TF , suggesting the incorporation of tumor‐derived MV s. Importantly, administration of an anti‐human TF mAb reduced clot size in tumor‐bearing mice but did not affect clot size in control mice. Conclusions Our results indicate that TF + MV s released from orthotopic pancreatic tumors increase venous thrombosis in mice. This new model may be useful for evaluating the roles of different factors in cancer‐associated thrombosis.