Judit Berta

National Koranyi Institute of TB and Pulmoology, Budapeŝto, Budapest, Hungary

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Publications (7)27.97 Total impact

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    ABSTRACT: Whereas the role of the G-protein-coupled APJ receptor and its ligand, apelin, in angiogenesis has been well documented, the ability of the apelin/APJ system to induce lymphangiogenesis and lymphatic metastasis has been largely unexplored. To this end, we first show that APJ is expressed in lymphatic endothelial cells (LECs) and, moreover, that it responds to apelin by activating the apelinergic signaling cascade. We find that although apelin treatment does not influence the proliferation of LECs in vitro, it enhances their migration, protects them against UV irradiation-induced apoptosis, increases their spheroid numbers in 3D culture, stimulates their in vitro capillary-like tube formation and, furthermore, promotes the invasive growth of lymphatic microvessels in vivo in the matrigel plug assay. We also demonstrate that apelin overexpression in malignant cells is associated with accelerated in vivo tumor growth and with increased intratumoral lymphangiogenesis and lymph node metastasis. These results indicate that apelin induces lymphangiogenesis and, accordingly, plays an important role in lymphatic tumor progression. Our study does not only reveal apelin as a novel lymphangiogenic factor but might also open the door for the development of novel anticancer therapies targeting lymphangiogenesis.
    Oncotarget 05/2014; · 6.63 Impact Factor
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    ABSTRACT: Recombinant human erythropoietins (rHuEPOs) are used to treat cancer-related anemia. Recent preclinical studies and clinical trials, however, have raised concerns about the potential tumor-promoting effects of these drugs. Because the clinical significance of erythropoietin receptor (EPOR) signaling in human non-small cell lung cancer (NSCLC) also remains controversial, our aim was to study whether EPO treatment modifies tumor growth and if EPOR expression has an impact on the clinical behavior of this malignancy. A total of 43 patients with stage III-IV adenocarcinoma (ADC) and complete clinicopathological data were included. EPOR expression in human ADC samples and cell lines was measured by quantitative real-time polymerase chain reaction. Effects of exogenous rHuEPOα were studied on human lung ADC cell lines in vitro. In vivo growth of human ADC xenografts treated with rHuEPOα with or without chemotherapy was also assessed. In vivo tumor and endothelial cell (EC) proliferation was determined by 5-bromo-2'-deoxy-uridine (BrdU) incorporation and immunofluorescent labeling. Although EPOR mRNA was expressed in all of the three investigated ADC cell lines, rHuEPOα treatment (either alone or in combination with gemcitabine) did not alter ADC cell proliferation in vitro. However, rHuEPOα significantly decreased tumor cell proliferation and growth of human H1975 lung ADC xenografts. At the same time, rHuEPOα treatment of H1975 tumors resulted in accelerated tumor endothelial cell proliferation. Moreover, in patients with advanced stage lung ADC, high intratumoral EPOR mRNA levels were associated with significantly increased overall survival. This study reveals high EPOR level as a potential novel positive prognostic marker in human lung ADC.
    PLoS ONE 01/2013; 8(10):e77459. · 3.53 Impact Factor
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    ABSTRACT: Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy. Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin. Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin. The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2011; 6(5):852-63. · 4.55 Impact Factor
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    ABSTRACT: The recently discovered bioactive peptide, apelin, has been demonstrated to stimulate angiogenesis in various experimental systems. However, its clinical significance and role in tumor vascularization have not yet been investigated in a human malignancy. Therefore, our aim was to study whether apelin expression is associated with angiogenesis and/or tumor growth/behavior in human non-small cell lung cancer (NSCLC). A total of 94 patients with stage I-IIIA NSCLC and complete follow-up information were included. Apelin expression in human NSCLC samples and cell lines was measured by quantitative reverse-transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. Effects of exogenous apelin and apelin transfection were studied on NSCLC cell lines in vitro. In vivo growth of tumors expressing apelin or control vectors were also assessed. Morphometric variables of human and mouse tumor capillaries were determined by anti-CD31 labeling. Apelin was expressed in all of the six investigated NSCLC cell lines both at the mRNA and protein levels. Although apelin overexpression or apelin treatments did not increase NSCLC cell proliferation in vitro, increasing apelin levels by gene transfer to NSCLC cells significantly stimulated tumor growth and microvessel densities and perimeters in vivo. Apelin mRNA levels were significantly increased in human NSCLC samples compared with normal lung tissue, and high apelin protein levels were associated with elevated microvessel densities and poor overall survival. This study reveals apelin as a novel angiogenic factor in human NSCLC. Moreover, it also provides the first evidence for a direct association of apelin expression with clinical outcome in a human cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 08/2010; 5(8):1120-9. · 4.55 Impact Factor
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    ABSTRACT: The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesion sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.
    Current Cancer Drug Targets 04/2010; 10(3):332-342. · 3.58 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.
    Current cancer drug targets 04/2010; 10(3):332-42. · 5.13 Impact Factor