ABSTRACT
Fibrinogen and platelets play an important role in cancer cell survival in the circulation by protecting cancer cells from the immune system. Moreover, endogenous activated protein C (APC) limits cancer cell extravasation due to sphingosine-1-phosphate receptor-1 (S(1)P(1)) and VE-cadherin-dependent vascular barrier enhancement. We aimed to study the relative contribution of these two mechanisms in secondary tumor formation in vivo. We show that fibrinogen depletion limits pulmonary tumor foci formation in an experimental metastasis model in C57Bl/6 mice but not in NOD-SCID mice lacking a functional immune system. Moreover, we show that in the absence of endogenous APC, fibrinogen depletion does not prevent cancer cell dissemination and secondary tumor formation in immune-competent mice. Overall, we thus show that endogenous APC is essential for immune-mediated cancer cell elimination.
Subject(s)
Protein C/metabolism , Animals , Antigens, CD/metabolism , Blood Coagulation , Blood Platelets/metabolism , Cadherins/metabolism , Fibrinogen/metabolism , Immune System , Lung Neoplasms/metabolism , Melanoma/metabolism , Melanoma, Experimental , Mice , Mice, Inbred C57BL , Mice, SCID , Neoplasm Metastasis , Protein C/immunology , Receptors, Lysosphingolipid/metabolism , Thrombin/metabolismSubject(s)
Neoplasms/drug therapy , Neoplasms/immunology , Thrombin/antagonists & inhibitors , Animals , Anticoagulants/pharmacology , Blood Coagulation , Disease Models, Animal , Disease Progression , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Melanoma, Experimental , Mice , Mice, SCID , Neoplasm Metastasis , Thrombin/immunologyABSTRACT
BACKGROUND: Inhibition of blood coagulation appears to be an important therapeutic strategy to improve the outcome in sepsis. However, the beneficial effect of anticoagulant treatment in sepsis is solely based on experimental data using inhibitors of the extrinsic coagulant pathway. The role of the intrinsic pathway of coagulation in the pathogenesis of sepsis has not been explored yet. OBJECTIVE: In the current study, we contribute to determine the role of factor (F)VIII, the key player of the intrinsic coagulant pathway, on host defense against peritonitis. METHOD: Hemizygous FVIII-deficient mice and their wild-type littermates were challenged with 1 x 10(4) bacteria in a septic peritonitis model. RESULTS: The intraperitoneal injection of Escherichia coli led to growth and dissemination of bacteria and provoked an inflammatory response as evident from elevated cytokine levels, increased cell influx into tissues, liver necrosis, and endothelialitis resulting in mortality. The FVIII-deficient genotype slightly reduced bacterial outgrowth but had no effect on markers of inflammation and/or survival. In addition, FVIII-deficient mice showed profound activation of coagulation, thereby improving the hemophilic phenotype of FVIII-deficient mice. CONCLUSION: FVIII deficiency slightly modifies host defense in septic peritonitis in mice, but does not influence the final outcome of peritonitis. Therefore, we question the importance of the intrinsic coagulant pathway during sepsis.
Subject(s)
Factor VIII/physiology , Hemophilia A , Peritonitis/etiology , Sepsis/etiology , Animals , Blood Coagulation , Colony Count, Microbial , Escherichia coli/growth & development , Hemophilia A/complications , Immunity , Inflammation , Lipoproteins/genetics , Mice , Peritonitis/blood , RNA, Messenger/analysis , Sepsis/blood , Survival Rate , Thromboplastin/geneticsABSTRACT
We present a newborn with glutathione synthetase deficiency and intracranial haemorrhages. Because the latter are rare in term newborns a possible relationship with glutathione synthetase deficiency will be discussed.
