Browsing by Subject "Angiogenesis"

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  • Theelen, Thomas L.; Lappalainen, Jari P.; Sluimer, Judith C.; Gurzeler, Erika; Cleutjens, Jack P.; Gijbels, Marion J.; Biessen, Erik A. L.; Daemen, Mat J. A. P.; Alitalo, Kari; Yla-Herttuala, Seppo (2015)
    Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B-100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8. To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p <0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p <0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Penttila, Patrick; Rautiola, Juhana; Poussa, Tuija; Peltola, Katriina; Bono, Petri (2017)
    Previous preclinical research suggests that angiotensin system inhibitors may have a direct anti-angiogenic effect that may be synergistic with the currently available angiogenesis inhibitors. In this retrospective study, we reviewed 303 patients with metastatic renal cell carcinoma treated with first-line angiogenesis inhibitors. Our results demonstrate a longer overall and progression-free survival for angiotensin system inhibitor users among patients with treatment-related hypertension. If validated, these results may guide the choice of antihypertensive medication among patients being treated with angiogenesis inhibitors. Background: Research suggests that baseline use of angiotensin system inhibitors (ASIs) improves outcome in patients with metastatic renal cell carcinoma (mRCC), but it remains unknown whether the type of antihypertensive medication used to initiate management at onset of treatment-induced hypertension (HTN) is associated with outcome. We evaluated the association of ASIs and outcome among patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs). Patients and Methods: We identified 303 consecutive patients with mRCC who were treated with sunitinib or pazopanib in a single university hospital cancer center. Statistical analyses were performed using the Kaplan-Meier method and Cox regression adjusted for known risk factors. Results: Progression-free survival (PFS) and overall survival (OS) were similar among patients with baseline HTN (n = 197; 65%) versus patients with no baseline HTN (n = 106; 35%) (PFS; P = .72) (OS; P = .54). There was a significant difference between patients with treatment-induced HTN (n = 110) versus patients with no treatment-induced HTN (n = 193) for PFS (15.6 vs. 6.4 months, respectively; P <.001) and OS (34.9 vs. 13.9 months, respectively; P <.001). Use of ASIs at baseline (n = 126; 41.6%) had no impact on outcome as compared with patients receiving other antihypertensive medication (n = 71; 23.4%) or with patients with no baseline antihypertensive medication (n = 106; 35.0%). Among patients with TKI-induced HTN (n = 110), however, ASI users (n = 91) demonstrated improved OS (37.5 vs. 18.1 months; P = .001) and PFS (17.1 vs. 7.2 months; P = .004) versus ASI nonusers (n = 19), respectively. Conclusion: Our results demonstrate survival benefit for ASI users among patients with TKI-induced HTN. These results, however, require further validation in a prospective setting. (C) 2016 Elsevier Inc. All rights reserved.
  • Tiainen, Leena; Korhonen, Emilia A.; Leppänen, Veli-Matti; Luukkaala, Tiina; Hämäläinen, Mari; Tanner, Minna; Lahdenperä, Outi; Vihinen, Pia; Jukkola, Arja; Karihtala, Peeter; Aho, Sonja; Moilanen, Eeva; Alitalo, Kari; Kellokumpu-Lehtinen, Pirkko-Liisa (2019)
    BackgroundAngiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer.MethodsPlasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6weeks and 6months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study.ResultsPlasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p
  • Tiainen, Leena; Korhonen, Emilia A; Leppänen, Veli-Matti; Luukkaala, Tiina; Hämäläinen, Mari; Tanner, Minna; Lahdenperä, Outi; Vihinen, Pia; Jukkola, Arja; Karihtala, Peeter; Aho, Sonja; Moilanen, Eeva; Alitalo, Kari; Kellokumpu-Lehtinen, Pirkko-Liisa (BioMed Central, 2019)
    Abstract Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p < 0.001). The overall survival of the patients with a high baseline Tie1 level was significantly shorter (multivariate HR 3.07, 95% CI 1.39–6.79, p = 0.005). Additionally, the progression-free survival was shorter for patients with a high baseline Tie1 level (multivariate HR 3.78, 95% CI 1.57–9.09, p = 0.003). In contrast, the baseline Ang2 levels had no prognostic impact in a multivariate Cox proportional hazard regression analysis. The combined analysis of baseline Tie1 and Ang2 levels revealed that patients with both high Tie1 and high Ang2 baseline levels had a significantly shorter overall survival than the patients with low baseline levels of both markers (multivariate HR for overall survival 4.32, 95% CI 1.44–12.94, p = 0.009). Conclusions This is the first study to demonstrate the prognostic value of baseline Tie1 plasma concentration in patients with metastatic breast cancer. Combined with the results of the Ang2 analyses, the patients with both high Tie1 and Ang2 levels before treatment had the poorest survival. Trial registration Clinicaltrials.gov: NCT00979641, registration date 19-DEC-2008. The regional Ethics Committee: R08142M, registration date 18-NOV-2008.
  • Grönman, Maria; Tarkia, Miikka; Kiviniemi, Tuomas; Halonen, Paavo; Kuivanen, Antti; Savunen, Timo; Tolvanen, Tuula; Teuho, Jarmo; Käkelä, Meeri; Metsälä, Olli; Pietilä, Mikko; Saukko, Pekka; Ylä-Herttuala, Seppo; Knuuti, Juhani; Roivainen, Anne; Saraste, Antti (BioMed Central, 2017)
    Abstract Background Radiolabeled RGD peptides detect αvβ3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvβ3 integrin is expressed in viable ischemic or injured myocardium. Methods We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. Results Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvβ3 integrin that was expressed in the injured myocardial areas. Conclusions Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvβ3 integrin expression associated with repair of recent myocardial injury.
  • Kinnunen, K.; Piippo, N.; Loukovaara, S.; Hytti, M.; Kaarniranta, K.; Kauppinen, A. (2017)
    Inflammation is a crucial component in the pathogenesis of many vascular diseases, such as atherosclerosis and diabetes. Inflammasomes are intracellular signalling complexes whose activation promotes inflammation. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) is a pattern recognition receptor (PRR) forming the best-known inflammasome. Disturbances in NLRP3 have been associated with multiple diseases. The purpose of this study was to explore the lysosomal destabilizationrelated NLRP3 inflammasome signaling pathway in human endothelial cells. In order to prime and activate NLRP3, human umbilical vein cells (HUVECs) were exposed to TNF-alpha and the lysosomal destructive agent Leusine-Leusine-OMethylesther (Leu-Leu-OMe), respectively. A caspase-1 inhibitor was used to block caspase-1' s enzymatic function and an interleukin 1 receptor antagonist (IL-1RA) to prevent any possible secondary effects of IL-1 beta. Leu-Leu-OMe increased the expression of NLRP3, IL-1 beta, and IL-18 in HUVECs. Exposure to Leu-Leu-OMe significantly promoted the production of IL-6 and IL-8 in primed HUVECs; this effect was prevented by the pre-treatment of cells with an IL-1RA. Our results suggest that lysosomal destabilization activates the NLRP3 inflammasome pathway that promotes the production of IL-6 and IL-8 in an autocrine manner in HUVEC cells.
  • Soderlund, Stina; Christiansson, Lisa; Persson, Inger; Hjorth-Hansen, Henrik; Richter, Johan; Simonsson, Bengt; Mustjoki, Satu; Olsson-Stromberg, Ulla; Loskog, Angelica (2016)
    Background and aims: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation. Methods: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek. Results: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX. Conclusions: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML. (C) 2016 Elsevier Ltd. All rights reserved.
  • Bersano, Anna; Guey, Stephanie; Bedini, Gloria; Nava, Sara; Herve, Dominique; Vajkoczy, Peter; Tatlisumak, Turgut; Saarela, Marika; van der Zwan, Albert; Klijn, Catharina J. M.; Braun, Kees P. J.; Kronenburg, Annick; Acerbi, Francesco; Brown, Martin M.; Calviere, Lionel; Cordonnier, Charlotte; Henon, Hilde; Thines, Laurent; Khan, Nadia; Czabanka, M.; Kraemer, Markus; Simister, Robert; Prontera, Paolo; Tournier-Lasserve, E.; Parati, Eugenio; European Moyamoya Dis Initiative (2016)
    Background: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. Summary: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. Key Message: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions. (C) 2016 S. Karger AG, Basel
  • Coles, Eric Anthony (Helsingin yliopisto, 2019)
    Tiivistelmä–Referat–Abstract Background: Cancer is one of the leading causes of death around the world and in Finland. Ambitious research projects have been carried out for decades investigating cancer and how it spreads. Over 35 years ago, the systems that regulate vascular formation were discovered; the vascular endothelial growth factor (VEGF)-VEGF receptor VEGFR system and the more recent Angiopoietin-TIE system. These are the main endothelial growth factor receptor pathways involved in regulation of vessel quiescence and angiogenesis. The VEGF-VEGFR system is the first discovered endothelial cell (EC) specific receptor tyrosine kinase (RTK) signaling system. VEGF is a major growth factor involved in proangiogenic activity and vascular permeability when bound to its receptor, VEGFR2. Tumor cells take advantage of the VEGF-VEGFR2 system by secreting VEGF to stimulate angiogenesis in surrounding tissue to create new blood vessels allowing for greater access to nutrients and oxygen for tumor growth. The Angiopoietin-TIE system is the second EC specific RTK signaling system that was discovered. Angiopoietin-1 (ANG1) is the ligand for the TIE2 RTK. ANG1 is an obligatory TIE2 agonist and its effects on intracellular signaling, cell cytoskeleton, and junction-related molecules allows ANG1 to restrict the amount and size of gaps that are formed at EC junctions in inflamed vessels, increasing barrier function and decreasing vascular permeability. Angiopoietin-2 (ANG2) is an autocrine context-dependent TIE2 agonist/antagonist which is implicated in stimulating pathological angiogenesis, inflammation and vascular permeability. Integrins are important cell surface receptors that all cells use to communicate with their environment. Recently, it has been discovered that ANG2 is capable of inducing pathological angiogenesis, and can destabilize ECs when bound to integrin, specifically β1-integrin, via ANG2 N-terminal region. Objectives: The general aim of this study was to discover which part of angiopoiten-2’s N-terminus region was responsible for integrin activation. Materials and Methods: Fibronectin fragment containing type III 7-10 domains was produced and fluorescently labeled with Alexa 647. Integrin activation was measured using the fluorescently labeled Fibronectin III 7-10 and angiopoietins. Fluorescence activated cell sorting (FACS) was used to collect the results, which were analyzed using excel. Chimeric angiopoietins were produced using retroviral vectors and used for FACS experiments. A cell internalization assay was performed in Hela cells using CellTracker™ Orange CMRA and angiopoietin proteins, stained with secondary antibody anti-human Alexa 488 and Texas Red Phallodin. Results: Optimization of the FACS assay defined the minimum number of cells required to reliably measure integrin activation and showed that BD Accuri FACS machine was better suited than Guarva FACS machine for the assay and that the amount of integrin varied between cell passages used for the assay. In addition, it was essential to ensure a homogenous mix of cells and recombinant proteins during the assay and the quality of the produced FN III 7-10 was critical for the success of the assay. Results from the FACS assay confirmed that ANG2 is capable of activating integrin. In addition, chimeric angiopoietins that were expressed and secreted from CHO cells, were capable of activating integrins to a variable degree. The results confirmed the importance of ANG2 N-terminus in integrin activation. Cell internalization assay visually demonstrated angiopoietin binding to Hela cells. ANG2 was internalized by the cell and resistant to the acid wash, while the majority of ANG1 bound to the cell surface was washed away by acid wash. Conclusions: In this thesis work, integrin activation assays were optimized and carried out, along with cell internalization assays, to determine which specific part of ANG2 is responsible for inducing integrin activation. The findings from this work confirmed that ANG2 is capable of activating integrin. Several chimeric constructs were successfully expressed in CHO cells, and the cell supernatants were used to activate integrins. However, more studies are needed to determine which specific region of ANG2 is responsible for integrin activation. Investigating angiopoietin induced integrin activation would allow for a better understanding of the angiopoietin signaling pathway with potential translational significance.
  • Bellou, Sofia; Karali, Evdoxia; Bagli, Eleni; Al-Maharik, Nawaf; Morbidelli, Lucia; Ziche, Marina; Adlercreutz, Herman; Murphy, Carol; Fotsis, Theodore (2012)