This thesis describes i) the function of an alternatively spliced coagulation factor in hemostasis, ii) the contribution of coagulation factors on cancer progression, and iii) expands our view... Show moreThis thesis describes i) the function of an alternatively spliced coagulation factor in hemostasis, ii) the contribution of coagulation factors on cancer progression, and iii) expands our view on cancer-associated thrombosis. Inhibition of Tissue Factor (TF) signaling with the antibody (Mab-10H10) resulted in decreased tumor initiating capacity and metastasis in a triple negative breast cancer (TNBC) cell line. Since this is a tumor type that is difficult to treat, and has high relapse-rates, it would be of interest to target TF signaling. Dual treatment of TNBC with conventional chemotherapy and Mab-10H10 could result in a positive treatment strategy as both highly proliferative and cancer stem cells are targeted. Furthermore, we provided a proof-of-principle study to search for novel biomarkers in patients with cancer-associated thrombosis in an unbiased manner. Up till now it is challenging to accurately predict those cancer patients with elevated risk of thrombosis. Furthermore, patients with cancer-associated thrombosis have poorer survival. Expansion of this study to validation cohorts and other tumor types will give insights in the underlying molecular mechanism of cancer-associated thrombosis. Eventually, this will aid a better prediction model to select those cancer patients with high risk of thrombosis and those who might benefit from thromboprophylaxis. Show less
Identification of translational and/or post-translational modifications of cardiac proteins after acute myocardial infarction (AMI) or during the progression to congestive heart failure (CHF) is... Show moreIdentification of translational and/or post-translational modifications of cardiac proteins after acute myocardial infarction (AMI) or during the progression to congestive heart failure (CHF) is relevant to gain insight into the pathological mechanisms. Characterization of the release kinetics of these cardiac proteins from the reversibly or irreversibly injured myocardium into the circulation may lead to new diagnostic biomarkers. Although cardiac Troponin I (cTnI) is a well-known biomarker of irreversible myocardial damage in acute myocardial infarction, we demonstrated that the release of cTnI also occurs from viable cardiomyocytes by a stretch-related mechanism, mediated by integrin stimulation. This finding may explain why in several pathological conditions, such as CHF, plasma cTnI levels are elevated in the absence of myocardial necrosis. In addition, we investigated the role of Tenascin-C re-expression during the development of heart failure and the relevance of TNC as a biomarker of ventricular remodeling. In animals with pressure-overload induced ventricle dilatation, TNC gene expression was upregulated, resulting in re-expression of myocardial TNC protein levels and elevated TNC plasma levels, correlating with cardiac function. Plasma TNC levels in patients with CHF declined during cardiac resynchronization therapy. This study indicates that serial plasma TNC levels can be used as a marker of adverse or reverse ventricular remodeling. Show less
