Malignant mesothelioma is a cancer, often originating from the pleura of the chest. There are no curative treatment options and systemic palliative treatments are scarce. It is suspected that the... Show moreMalignant mesothelioma is a cancer, often originating from the pleura of the chest. There are no curative treatment options and systemic palliative treatments are scarce. It is suspected that the growth process in mesothelioma is highly dependent on the creation of new vessels stimulated by the tumour itself, also called angiogenesis. In this thesis, 2 drugs that inhibit angiogenesis were tested aiming at improving progression-free survival (PFS). Thalidomide was given as a maintenance treatment after first-line chemotherapy in a large randomised study. Axitinib was given in combination with first-line chemotherapy in a smaller randomised trial, in which we included pre- and post-treatment biopsies. The vascularisation of the tumour and the possible influence of vascular growth factors were examined. In the translational part of this study, we showed that axitinib treatment efficiently prevented tumour neovascularisation. However, this did not improve PFS. The thalidomide study also showed no benefit in PFS or survival. Meanwhile the literature has shown that many angiogenesis inhibitors do not achieve a positive result either. We will have to look for other treatment options to improve the prognosis of mesothelioma patients. Show less
This thesis describes the role of 14q32 microRNAs in vascular remodelling. The 14q32 microRNA cluster contains 54 microRNAs in humans and is highly conserved in mammals. In part I of this thesis,... Show moreThis thesis describes the role of 14q32 microRNAs in vascular remodelling. The 14q32 microRNA cluster contains 54 microRNAs in humans and is highly conserved in mammals. In part I of this thesis, we describe the role of 14q32 microRNAs in several processes of vascular remodelling. We have shown that inhibition of several 14q32 microRNAs, miR-329, miR-494 and miR-495, results in increased neovascularisation after hindlimb ischemia in mice. In addition, inhibition of the same microRNAs reduced atherosclerotic plaque formation and restenosis in experimental mouse models under hypercholesterolemic conditions. In part II of this thesis, we zoom in to the post-transcriptional regulation of 14q32 microRNAs through RNA binding proteins. The third and last part of this thesis studies the expression of microRNAs in subcutaneous adipose tissue of critical limb ischemia patients and discusses the potential use of microRNAs as biomarker to predict the risk of amputation in these patients. In conclusion, this thesis provides novel insights in the role of 14q32 microRNAs in processes of vascular remodelling. Experimental studies have identified 14q32 microRNAs as potential therapeutic targets for treatment and prevention of atherosclerosis, restenosis and peripheral arterial disease. Show less
