Cancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental... Show moreCancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental in order to develop effective therapeutics. At the molecular level, signaling pathways control cell growth, differentiation or apoptosis during development and adult life of the organism ensuring homeostasis. Paradoxically, the same signals are often implicated or even drive disease progression. One of the signaling pathways with key regulatory functions in homeostasis, tissue fibrosis and cancer in many organs is the TGFβ/BMP pathway. In this thesis we addressed the role and therapeutic potential of TGFβ/BMP pathway inhibition using different drug compounds that are currently towards the clinic or being tested in clinical trials. Three distinct types of inhibitors were used; small molecule inhibitors of the ALK4, 5 and 7 TGFβ receptor kinases, an antisense oligonucleotide interfering with ALK5 mRNA splicing and an ALK1 ligand trap; a peptide that contains the extracellular domain of ALK1 fused to Fc and sequesters BMP9 and BMP10. These inhibitors were used in an ex vivo human fibrosis model and in vivo mouse models of various human diseases (acute liver failure/ liver regeneration, Dupuytren's fibrosis) and cancer (prostate, liver). Show less
Buijs, J.T.; Matula, K.M.; Cheung, H.; Kruithof-de Julio, M.; Mark, M.H. van der; Snoeks, T.J.; ... ; Pluijm, G. van der 2015
The transforming growth factor (TGF)-_ signalling pathway plays a major role in angiogenesis. Aberration of the TGF-_ signalling cascade leads to abnormal remodelling and maturation of the... Show moreThe transforming growth factor (TGF)-_ signalling pathway plays a major role in angiogenesis. Aberration of the TGF-_ signalling cascade leads to abnormal remodelling and maturation of the primitive vascular plexus and decreased vessel wall integrity in adults. Targeted deletion of TGF-_ signalling receptors in mice, such as ALK1, ALK5, T_RII or endoglin, results in embryonic lethality due to impaired vascular development. In humans, mutations in ALK1, ALK5, T_RII or endoglin are associated with human vascular diseases such as HHT and pulmonary hypertension (PAH). Vascular endothelial growth factor (VEGF) is a multifunctional molecule that is involved in vascular growth and remodeling. Perturbation in VEGF signalling also contributes to the pathology of tumor angiogenesis and cardiovascular diseases in humans. This thesis is focused on the characterization of the crosstalk between the TGF-_ and VEGF signalling pathways, on EC function, the effect of bone morphogenetic protein (BMP)9 on EC function and the role of endoglin in VEGF-induced angiogenesis. The results of these studies may give us insights into the impacts/effects of these two angiogenic signalling cascades on EC function. This can be beneficial for the understanding of the etiology of certain vascular diseases and the development of new treatment modalities in the future Show less
