The TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth... Show moreThe TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth factors and cytokines that exert either pro- or anti-tumor effects. This thesis mainly focuses on studies of the TME, especially the effects of Endoglin, on several cell types within the TME, including endothelial cells, fibroblasts, and immune cells.The TME has increasingly been recognized as an important player in tumor progression and metastasis and a possible target for therapy. The TME consists of multiple cell types secreting growth factors and cytokines that exert either pro- or anti-tumor effects. This thesis mainly focusses on studies of the TME, especially the effects of Endoglin, on several cell types within the TME, including endothelial cells, fibroblasts, and immune cells. This thesis aims to unravel the role of Endoglin as a possible target on various cell types within the TME of solid tumors. Endoglin is known for its role during angiogenesis, however, an increasing number of studies have shown the importance of Endoglin expression on several other cell types (e.g., immune cells, CAFs, tumor cells). Show less
Myocardial infarction results in a permanent loss of function in the heart. Currently, there is no therapy available that addresses the heart of the problem: the loss of cardiomyocytes. Cell... Show moreMyocardial infarction results in a permanent loss of function in the heart. Currently, there is no therapy available that addresses the heart of the problem: the loss of cardiomyocytes. Cell transplantation has been a focus of cardiac regenerative studies. Interestingly, cell transplantation has effect on cardiac function and vessel formation in the absence of cardiac differentiation, suggesting a role for the paracrine factors. Besides replacing cardiomyocytes, restoring blood flow to the infarcted area is vital. We showed that vasculogenesis is not hampered by the loss of endoglin, but angiogenesis, and network formation was impaired with reduced endoglin expression. We also studied the effect of extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSC) and cardiac progenitor cells (CPC) on angiogenesis and infarct size. Both in vitro and in vivo angiogenesis was significantly improved in the presence of these EVs. Knockdown of the pro-angiogenic factor EMMPRIN resulted in a reduction in angiogenesis. Injection of the CPC derived EVs into the heart after MI resulted in a decrease in infarct size. Furthermore, total proliferation was increase in the border zone and infarcted area as seen by an increase in Ki67 and Yap. These results show therapeutic potential of EVs for cardiac regeneration. Show less
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and... Show moreHereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease, is a rare genetic disorder, known for its endothelial dysplasia causing vessel malformations, severe nose bleeds and internal bleedings. In the majority of patients mutations are found in genes belonging to the TGFβ superfamily, causing a disbalance in the TGFβ signaling pathway by haploinsufficiency of the remaining functional protein. In this thesis we studied different aims and approaches to influence HHT1-MNC homing and differentiation to restore their contribution to tissue repair. In various experimental methods inducing ischemic and/or direct tissue damage, we aimed to improve tissue repair in the Eng+/- mice. Using DPP4 inhibition, we increased the SDF1-CXCR4 homing mechanism, to restore the impaired homing capacity of the HHT1-MNCs. Furthermore, we focused on correcting the M1/M2 differentiation in Eng+/- mice. Via use of the BMP receptor inhibitor LDN we aimed to restore the skewed BMP/TGFβ signaling; stimulating the TGFβ pathway signaling to induce M2 differentiation. We concluded that DPP4 inhibition can be used to improve the HHT1 immune system and tissue repair, and is best used in concert with other drugs or therapies that stimulate cardiac or tissue repair, like anti-coagulants or cell therapy. Show less
Cell transplantation studies have shown that injection of progenitor cells can improve cardiac function after myocardial infarction (MI). Transplantation of human cardiac progenitor cells (hCPCs)... Show moreCell transplantation studies have shown that injection of progenitor cells can improve cardiac function after myocardial infarction (MI). Transplantation of human cardiac progenitor cells (hCPCs) results in an increased ejection fraction, but survival and integration are low. Therefore, paracrine factors including extracellular vesicles (EVs) are likely to contribute to the beneficial effects. We investigated the contribution of EVs by transplanting hCPCs with reduced EV secretion. Interestingly, these hCPCs were unable to reduce infarct size post-MI. Moreover, injection of hCPC-EVs did significantly reduce infarct size. Analysis of EV uptake showed cardiomyocytes and endothelial cells primarily positive and a higher Ki67 expression in these cell types. Yes-associated protein (YAP), a proliferation marker associated with Ki67, was also increased in the entire infarcted area. In summary, our data suggest that EV secretion is the driving force behind the short-term beneficial effect of hCPC transplantation on cardiac recovery after MI. Show less
In dit proefschrift worden studies besproken naar de rol van de TGF-β signaleringsroute in de tumor micro-omgeving in colorectaal kanker. Deze studies hebben zich voornamelijk gefocust op de rol... Show moreIn dit proefschrift worden studies besproken naar de rol van de TGF-β signaleringsroute in de tumor micro-omgeving in colorectaal kanker. Deze studies hebben zich voornamelijk gefocust op de rol van kanker-geassocieerde fibroblasten (CAFs) in kanker. Wij hebben aangetoond dat een co-receptor voor TGF-β, endoglin, een grote rol speelt in het CAF-gemedieerd uitzaaien van darmkanker en dat de expressie van endoglin op CAFs een prognostische marker is voor metastase-vrije overleving in vroeg stadium darmkankerpatienten. Daarnaast werd een nieuwe muizenstam ontwikkeld om specifiek op fibroblasten endoglin uit te schakelen, zodat de rol hiervan in het ontstaan van darmkanker bestudeerd kon worden in een chemisch geinduceerd model voor darmkanker. Samengevat laten de studies in dit proefschrift zien dat endoglin expressie op CAFs een belangrijke rol speelt in het metastaseren van colorectaalkanker en opent het deuren naar therapeutische toepassingen. Show less
Cortie, K. de; Russell, N.S.; Coppes, R.P.; Stewart, F.A.; Scharpfenecker, M. 2014
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
Maring, J.A.; Trojanowska, M.; Dijke, P. ten; Jeon, K.W. 2012
Clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is... Show moreClinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is necessary for optimum management of patients with these complex tumors. Although markers for GEP-NETs exist, sensitive and specific markers that predict tumor growth and behaviour are lacking. The general purpose of the studies described in this thesis was to investigate the epidemiology, diagnosis and pathogenesis of GEP-NETs in The Netherlands, to reveal insights in the pathological mechanisms contributing to the development and progression of these tumors. Not only worldwide but also in The Netherlands, the incidence of these tumors is increasing. The diverse studies contribute to a better understanding of the role of angiogenesis, neuropeptides and matrix metallo-proteinases in neuroendocrine tumors of the digestive tract and pancreas. Additional studies and further research will possible lead to new diagnostic and therapeutic implications of endoglin, bombesin and MMPs in patients with gastroenteropancreatic neuroendocrine tumors. Show less
