Browsing by Subject "Angiopoietin-2"

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  • Hintsala, Emilia (Helsingfors universitet, 2010)
    TAUSTA: Syöpään liittyvää angiogeneesiä eli verisuonten uudismuodostusta on tutkittu hyvin paljon mm. mahdollisena syöpähoitojen kohteena. Kiinteissä kasvaimissa ja leukemioissa on havaittu esimerkiksi angiogeneesiä säätelevien molekyylien tuotannon ja syöpäkudoksen ympäristön hiussuonitiheyden lisääntymistä. Tämän tutkimuksen tarkoituksena oli selvittää kahden angiogeneesiä säätelevän molekyylin, VEGF:n ja Angiopoietiini-2:n, pitoisuuksia lapsisyöpäpotilailla. METODIT: Määritimme VEGF- ja Angiopoietiini-2-pitoisuudet 49 kiinteäkasvainpotilaan plasmanäytteistä ja 35 leukemiapotilaan plasma- ja luuydinnäytteistä diagnoosivaiheessa ja hoidon aloittamisen jälkeen. TULOKSET: Kiinteäkasvainryhmässä mitattiin korkeampia VEGF-pitoisuuksia kuin leukemiaryhmässä ja pitoisuudet laskivat hoidon aloittamisen seurauksena. Leukemiaryhmässä mitattiin kiinteitä kasvaimia korkeampia Angiopoietiini-2-pitoisuuksia ja pitoisuudet laskivat hoidon aikana. Leukemiapotilailla hoidon aloittamisen jälkeen todettu korkea luuytimen VEGF-pitoisuus liittyi matalampaan elossaolo-osuuteen. VEGF- ja Angiopoietiini-2-pitoisuudet korreloivat plasma- ja luuydinnäytteiden välillä. Diagnoosivaiheessa lymfoomapotilailla oli korkeampia ja aivokasvainpotilailla matalampia Angiopoietiini-2-pitoisuuksia kuin muilla kiinteäkasvainpotilailla ja AML-potilailla korkeampia VEGF-pitoisuuksia kuin ALL-potilailla. PÄÄTELMÄT: Tutkimus antaa uutta tietoa lapsisyöpäpotilaiden angiogeneettisistä tekijöistä. VEGF- ja Angiopoietiini-2-pitoisuuksissa havaittiin eroja eri syöpätyyppien välillä ja muutoksia hoidon aloittamisen seurauksena. VEGF-pitoisuudella oli myös ennusteellista merkitystä.
  • Kallio, Pauliina; Jokinen, Elina; Das, Suvendu; Högström, Jenny; Heino, Sarika; Lähde, Marianne; Alitalo, Kari (Helsingin yliopisto, 2018)
    Radiation induced tumor cell death is strongly dependent on oxygen. As abnormal tumor vasculature promotes tumor hypoxia, drugs that induce vascular normalization, such as the anti-vascular endothelial growth factor (VEGF) antibody, have been tested as radiation sensitizers in preclinical and clinical settings. The insufficient benefit obtained with anti-VEGF therapy prompted us to test if antibodies blocking the endothelial growth factor angiopoietin-2 (Ang2) could improve the effect of radiation in mouse tumor allografts and human tumor xenografts. Mouse or human tumor cells were injected subcutaneously in isogenic immunocompetent or immunodeficient (NSG) mice, respectively, and tumors were allowed to form. The mice were injected with anti-Ang2 or control antibodies every three or four days starting three days before 3x2 Gy or 4x0.5 Gy whole-body radiation, followed by analysis of tumor growth, histology, vasculature, hypoxia and necrosis. Combination treatment with anti-Ang2 and radiation improved tumor growth inhibition and extended the survival of mice with melanoma or colorectal carcinoma allografts. A similar anti-Ang2 plus radiation response was also obtained in immunodeficient mice implanted with a human colorectal carcinoma xenograft, indicating that the adaptive immune response was not essential for the effect. Histological and immunohistochemical analysis of the tumors showed that the combination treatment decreased tumor vasculature, and increased tumor hypoxia and tumor necrosis in comparison with control tumors and tumors treated with the monotherapies. Our results suggest that a combination of Ang2 blocking antibodies and radiation increases tumor growth inhibition and extends the survival of tumor-bearing mice. Significance: These findings offer a preclinical rationale for further testing of the use of Ang2 blocking antibodies in combination with radiation to improve the overall outcome of cancer treatment.
  • 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.
  • 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.