title: Tissue factor-activated coagulation cascade in the tumor microenvironment is critical for tumor progression and an effective target for therapy.
abstract: Tissue factor (TF), a rate-limiting enzyme cofactor in activating coagulation, is highly expressed in a wide spectrum of human tumor and tumor stromal cells. Using TF-deficient cancer cells and a conditional TF-knockout mouse model, we show that TF expressed by cancer cells, but not by the host stromal cells, plays a critical role in tumor growth. In the tumor microenvironment, serum coagulation factors are readily extravasated and therefore lead to continuous TF-mediated activation of coagulation proteases. To target this highly specific cascade of serine proteases, we used both a TF:VIIa inhibitor and doxorubicin-based prodrugs that are selectively activated by TF:FVIIa, FXa, and thrombin. Treatment with the TF:FVIIa inhibitor led to growth retardation in breast tumor models. In contrast, treatment with the prodrug eliminated primary tumor cells and lung metastases without apparent toxicity. Our findings offer preclinical proof of principle that targeting the coagulation cascade that is activated in the tumor microenvironment can be a highly effective approach for cancer therapy.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
authors: Yuan
authors: Y
authors: Liu
authors: Pengfei
authors: P
authors: Jiang
authors: Katerina
authors: K
authors: Capkova
authors: Dong
authors: D
authors: Xue
authors: Longwu
authors: L
authors: Ye
authors: Subhash C
authors: SC
authors: Sinha
authors: Nigel
authors: N
authors: Mackman
authors: Kim D
authors: KD
authors: Janda
authors: Cheng
authors: C
authors: Liu
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018450:Disease Progression; D004317:Doxorubicin / Q000378:metabolism / Q000627:therapeutic use; D015942:Factor VIIa / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D001779:Blood Coagulation Factors; D011355:Prodrugs; D004317:Doxorubicin; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin