References of "Tabruyn, Sébastien"
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See detailNF-kappaB activation in endothelial cells is critical for the activity of angiostatic agents.
Tabruyn, Sébastien ULg; Memet, Sylvie; Ave, Patrick et al

in Molecular Cancer Therapeutics (2009), 8(9), 2645-54

In tumor cells, the transcription factor NF-kappaB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth ... [more ▼]

In tumor cells, the transcription factor NF-kappaB has been described to be antiapoptotic and proproliferative and involved in the production of angiogenic factors such as vascular endothelial growth factor. From these data, a protumorigenic role of NF-kappaB has emerged. Here, we examined in endothelial cells whether NF-kappaB signaling pathway is involved in mediating the angiostatic properties of angiogenesis inhibitors. The current report describes that biochemically unrelated agents with direct angiostatic effect induced NF-kappaB activation in endothelial cells. Our data showed that endostatin, anginex, angiostatin, and the 16-kDa N-terminal fragment of human prolactin induced NF-kappaB activation in endothelial cells in both cultured human endothelial cells and in vivo in a mouse tumor model. It was also found that NF-kappaB activity was required for the angiostatic activity, because inhibition of NF-kappaB in endothelial cells impaired the ability of angiostatic agents to block sprouting of endothelial cells and to overcome endothelial cell anergy. Therefore, activation of NF-kappaB in endothelial cells can result in an unexpected antitumor outcome. Based on these data, the current approach of systemic treatment with NF-kappaB inhibitors may therefore be revisited because NF-kappaB activation specifically targeted to endothelial cells might represent an efficient strategy for the treatment of cancer. [less ▲]

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See detailCellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors.
Sennino, Barbara; Kuhnert, Frank; Tabruyn, Sébastien ULg et al

in Cancer Research (2009), 69(10), 4527-36

Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear ... [more ▼]

Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels. [less ▲]

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See detailStudy of the role of Sprouty1 in the regulation of angiogenesis
Sabatel, Céline; Tabruyn, Sébastien ULg; Cornet, Anne et al

Poster (2008, March 30)

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See detailAngiostatic activity of the antitumor cytokine interleukin-21.
Castermans, Karolien ULg; Tabruyn, Sébastien ULg; Zeng, Rong et al

in Blood (2008), 112(13), 4940-7

Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ... [more ▼]

Interleukin-21 (IL-21) is a recently described immunoregulatory cytokine. It has been identified as a very potent immunotherapeutic agent in several cancer types in animal models, and clinical studies are ongoing. IL-21 belongs to the type I cytokine family of which other members, ie, IL-2, IL-15, and IL-4, have been shown to exert activities on vascular endothelial cells (ECs). We hypothesized that IL-21, in addition to inducing the antitumor immune response, also inhibits tumor angiogenesis. In vitro experiments showed a decrease of proliferation and sprouting of activated ECs after IL-21 treatment. We found that the IL-21 receptor is expressed on vascular ECs. Furthermore, in vivo studies in the chorioallantoic membrane of the chick embryo and in mouse tumors demonstrated that IL-21 treatment disturbs vessel architecture and negatively affects vessel outgrowth. Our results also confirm the earlier suggested angiostatic potential of IL-2 in vitro and in vivo. The angiostatic effect of IL-21 is confirmed by the decrease in expression of angiogenesis-related genes. Interestingly, IL-21 treatment of ECs leads to a decrease of Stat3 phosphorylation. Our research shows that IL-21 is a very powerful antitumor compound that combines the induction of an effective antitumor immune response with inhibition of tumor angiogenesis. [less ▲]

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See detailNF-kappa B: a new player in angiostatic therapy.
Tabruyn, Sébastien ULg; Griffioen, Arjan W

in Angiogenesis (2008), 11(1), 101-6

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on ... [more ▼]

Angiogenesis is considered a promising target in the treatment of cancer. Most of the angiogenesis inhibitors in late-stage clinical testing or approved for the treatment of cancer act indirectly on endothelial cells. They either neutralize angiogenic growth factors from the circulation or block the signaling pathways activated by these growth factors. Another group of angiogenesis inhibitors are the direct angiostatic compounds. These agents have a direct effect on the endothelium, affecting cellular regulatory pathways, independently of the tumor cells. The reason that this category of agents is lagging behind regarding their translation to the clinic may be the lack of sufficient knowledge on the mechanism of action of these compounds. The transcription factor NF-kappaB has been recently connected with multiple aspects of angiogenesis. In addition, several recent studies report that angiogenesis inhibition is associated to NF-kappaB activation. This is of special interest since in tumor cells NF-kappaB activation has been associated to inhibition of apoptosis and currently novel treatment strategies are being developed based on inhibition of NF-kappaB. The paradigm that systemic NF-kappaB inhibition can serve as an anti-cancer strategy, therefore, might need to be re-evaluated. Based on recent data, it might be speculated that NF-kappaB activation, when performed specifically in endothelial cells, could be an efficient strategy for the treatment of cancer. [less ▲]

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See detailInhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL
Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg; Blacher, Silvia ULg et al

in Molecular Therapy : The Journal of the American Society of Gene Therapy (2007), 15(12), 2094-2100

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic ... [more ▼]

Tumor metastases, the most fearsome aspect of cancer, are generally resistant to conventional therapies. Angiogenesis is a crucial aspect of tumor growth and metastatic dissemination. Antiangiogenic therapy, therefore, holds potential as an attractive strategy for inhibiting metastasis development. Human 16K PRL (16K hPRL), a potent inhibitor of angiogenesis, has been demonstrated to prevent tumor growth in two xenograft mouse models, but whether it also affects tumor metastasis is unknown. In this study we will investigate the ability of 16K hPRL to prevent the establishment of metastasis. We demonstrate that 16K hPRL administered via adenovirus-mediated gene transfer, inhibits tumor growth by 86% in a subcutaneous (SC) B16-F10 mouse melanoma model. Computer-assisted image analysis shows that 16K hPRL treatment results in a reduction of tumor-vessel length and width, leading to a 57% reduction of average vessel size. In a pre-established tumor model, moreover, 16K hPRL can significantly delay tumor development. Finally, for the first time, we provide evidence that 16K hPRL considerably reduces the establishment of B16-F10 metastasis in an experimental lung metastasis model. Both the number and size of metastases are reduced by 50% in 16K hPRL-treated mice. These results highlight a potential role for 16K hPRL in anticancer therapy for both primary tumors and metastases. [less ▲]

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See detailIntrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells
Verhaeghe, Catherine ULg; Tabruyn, Sébastien ULg; Oury, Cécile ULg et al

in Biochemical and Biophysical Research Communications (2007), 356(3), 745-749

Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been ... [more ▼]

Cystic fibrosis is a common genetic disorder characterized by a severe lung inflammation and fibrosis leading to the patient's death. Enhanced angiogenesis in cystic fibrosis (CF) tissue has been suggested, probably caused by the process of inflammation, as similarly described in asthma and chronic bronchitis. The present study demonstrates an intrinsic pro-angiogenic status of cystic fibrosis airway epithelial cells. Microarray experiments showed that CF airway epithelial cells expressed several angiogenic factors such as VEGF-A, VEGF-C, bFGF, and PLGF at higher levels than control cells. These data were confirmed by real-time quantitative PCR and, at the protein level, by ELISA. Conditioned media of these cystic fibrosis cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. This report describes for the first time that cystic fibrosis epithelial cells have an intrinsic angiogenic activity. Since excess of angiogenesis is correlated with more severe pulmonary disease, our results could lead to the development of new therapeutic applications. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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See detailThe angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-kappaB activation
Tabruyn, Sébastien ULg; Sabatel, Céline ULg; Nguyen, Ngoc-Quynh-Nhu ULg et al

in Molecular Endocrinology (2007), 21(6), 1422-9

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent angiostatic factor that inhibits tumor growth in mouse models. Using microarray experiments, we have dissected how the endothelial ... [more ▼]

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent angiostatic factor that inhibits tumor growth in mouse models. Using microarray experiments, we have dissected how the endothelial-cell genome responds to 16K hPRL treatment. We found 216 genes that show regulation by 16K hPRL, of which a large proportion turned out to be associated with the process of immunity. 16K hPRL induces expression of various chemokines and endothelial adhesion molecules. These expressions, under the control of nuclear factor-kappaB, result in an enhanced leukocyte-endothelial cell interaction. Furthermore, analysis of B16-F10 tumor tissues reveals a higher expression of adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, or E-selectin) in endothelial cells and a significantly higher number of infiltrated leukocytes within the tumor treated with 16K hPRL compared with the untreated ones. In conclusion, this study describes a new antitumor mechanism of 16K hPRL. Because cellular immunity against tumor cells is a crucial step in therapy, the discovery that treatment with 16K hPRL overcomes tumor-induced anergy may become important for therapeutic perspectives. [less ▲]

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See detailA new role for NF-kappaB in angiogenesis inhibition.
Tabruyn, Sébastien ULg; Griffioen, A. W.

in Cell Death & Differentiation (2007), 14(8), 1393-7

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See detailMolecular pathways of angiogenesis inhibition.
Tabruyn, Sébastien ULg; Griffioen, Arjan W

in Biochemical and Biophysical Research Communications (2007), 355(1), 1-5

A large body of evidence now demonstrates that angiostatic therapy represents a promising way to fight cancer. This research recently resulted in the approval of the first angiostatic agent for clinical ... [more ▼]

A large body of evidence now demonstrates that angiostatic therapy represents a promising way to fight cancer. This research recently resulted in the approval of the first angiostatic agent for clinical treatment of cancer. Progress has been achieved in decrypting the cellular signaling in endothelial cells induced by angiostatic agents. These agents predominantly interfere with the molecular pathways involved in migration, proliferation and endothelial cell survival. In the current review, these pathways are discussed. A thorough understanding of the mechanism of action of angiostatic agents is required to develop efficient anti-tumor therapies. [less ▲]

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See detailMolecular profiling of 16K PRL treated tumours by an antibody-array approach
Cornet, Anne ULg; Nguyen, Ngoc-Quynh-Nhu ULg; Lion, Michelle ULg et al

Poster (2006, May)

Tumour development is often accompanied by the formation of new blood vessels from existing vasculature. This new intratumoral blood network is driven by the process of angiogenesis, providing the ... [more ▼]

Tumour development is often accompanied by the formation of new blood vessels from existing vasculature. This new intratumoral blood network is driven by the process of angiogenesis, providing the essential nutrients for growth, invasion and metastasis. At the present time, it is well established that inhibitors of angiogenesis prevent the growth and progression of tumours, offering a new therapeutic approach for treatment of cancer. Several studies have already showed that the N-terminal fragment of the human prolactin, 16k-Da PRL, has a potent anti-angiogenic activity. Recently, research groups have demonstrated that the 16k-Da PRL inhibits tumour development in animal models. Despite the fact that several studies leading to improve our knowledge of 16k-Da PRL action were performed, little is known about its role played to prevent tumour growth in vivo. In this study, we first tested the ability of the 16k-Da PRL to inhibit the growth of established HCT116 tumours in nude mice, using an adenovirus approach. As expected, we found that the tumour progression was tightly reduced by the expression of the 16k-Da PRL into the tumours. This antitumour activity was also associated with a slight tumour vascularization. To discover biomarkers that contribute in 16k-Da PRL tumour suppressive effects, we used one of the most powerful multiplexed detection techonologies: the antibody-microarray proposed by Eurogentec. These protein-chips allow to identify multiple proteins from small amounts of samples within a single experiment. Three independent sets of antibody array from samples of 16k-Da PRL treated tumours and controls were analysed. Experimental and analysis optimisations were applied to ensure the correct interpretation of the fluorescent signals from the antibody arrays. In addition, significant results were confirmed by Western blot analysis. Our study allowed to identify several proteins which could be implicated in the tumour dormancy induced by 16k-Da PRL treatment. Additional analysis will provide important biological information for discovering of the new cancer biomarkers and their relationship with the 16k-Da PRL effects on cancer development. [less ▲]

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See detailRaloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.
Olivier, Sabine ULg; Close, Pierre ULg; Castermans, Emilie ULg et al

in Molecular Pharmacology (2006), 69(5), 1615-1623

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of ... [more ▼]

Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-kappaB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma. [less ▲]

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See detailProlactin/growth hormone-derived antiangiogenic peptides highlight a potential role of tilted peptides in angiogenesis
Nguyen, Ngoc-Quynh-Nhu ULg; Tabruyn, Sébastien ULg; Lins, Laurence ULg et al

in Proceedings of the National Academy of Sciences of the United States of America (2006), 103(39), 14319-14324

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short ... [more ▼]

Angiogenesis is a crucial step in many pathologies, including tumor growth and metastasis. Here, we show that tilted peptides exert antiangiogenic activity. Tilted (or oblique-oriented) peptides are short peptides known to destabilize membranes and lipid cores and characterized by an asymmetric distribution of hydrophobic residues along the axis when helical. We have previously shown that 16-kDa fragments of the human prolactin/growth hormone (PRL/GH) family members are potent angiogenesis inhibitors. Here, we demonstrate that all these fragments possess a 14-aa sequence having the characteristics of a tilted peptide. The tilted peptides of human prolactin and human growth hormone induce endothelial cell apoptosis, inhibit endothelial cell proliferation, and inhibit capillary formation both in vitro and in vivo. These antiangiogenic effects are abolished when the peptides' hydrophobicity gradient is altered by mutation. We further demonstrate that the well known tilted peptides of simian immunodeficiency virus gp32 and Alzheimer's beta-amyloid peptide are also angiogenesis inhibitors. Taken together, these results point to a potential new role for tilted peptides in regulating angiogenesis. [less ▲]

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See detailThe antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G(0)-G(1) and the G(2)-M phases
Tabruyn, Sébastien ULg; Nguyen, Ngoc-Quynh-Nhu ULg; Cornet, Anne ULg et al

in Molecular Endocrinology (2005), 19(7), 1932-1942

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate ... [more ▼]

The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate that 16K hPRL inhibits serum-induced DNA synthesis in adult bovine aortic endothelial cells. This inhibition is associated with cell cycle arrest at both the G(0)-G(1) and the G(2)-M phase. Western blot analysis revealed that 16K hPRL strongly decreases levels of cyclin D1 and cyclin B1, but not cyclin E. The effect on cyclin D1 is at least partially transcriptional, because treatment with 16K hPRL both reduces the cyclin D1 mRNA level and down-regulates cyclin D1 promoter activity. This regulation may be due to inhibition of the MAPK pathway, but it is independent of the glycogen synthase kinase-3 beta pathway. Lastly, 16K hPRL induces the expression of negative cell cycle regulators, the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1). In summary, 16K hPRL inhibits serum-induced proliferation of endothelial cells through combined effects on positive and negative regulators of cell cycle progression. [less ▲]

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