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      Rosuvastatin Counteracts Vessel Arterialisation and Sinusoid Capillarisation, Reduces Tumour Growth, and Prolongs Survival in Murine Hepatocellular Carcinoma

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          Background and Aims. An arterial blood supply and phenotypic changes of the sinusoids characterise the liver vasculature in human hepatocellular carcinoma (HCC). We investigated the effects of rosuvastatin on liver vessel anomalies, tumour growth and survival in HCC. Methods. We treated transgenic mice developing HCC, characterized by vessel anomalies similar to those of human HCC, with rosuvastatin. Results. In the rosuvastatin group, the survival time was longer ( P < .001), and liver weight ( P < .01) and nodule surface ( P < .01) were reduced. Rosuvastatin decreased the number of smooth muscle actin-positive arteries ( P < .05) and prevented the sinusoid anomalies, with decreased laminin expression ( P < .001), activated hepatic stellate cells ( P < .001), and active Notch4 expression. Furthermore, rosuvastatin inhibited endothelial cell but not tumour hepatocyte functions. Conclusions. Rosuvastatin reduced the vessel anomalies and tumour growth and prolonged survival in HCC. These results represent new mechanisms of the effects of statin on tumour angiogenesis and a potential target therapy in HCC.

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          Most cited references 37

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          Statins and cancer prevention.

          Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.
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            Statins have biphasic effects on angiogenesis.

            Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
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              Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease.

              Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies. Copyright 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Gastroenterol Res Pract
                Gastroenterology Research and Practice
                Hindawi Publishing Corporation
                22 February 2011
                : 2010
                1Institut des Vaisseaux et du Sang, Hôpitlal Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                2“Angiogenèse et Recherche Translationnelle” INSERM U 965 “Equipe labellisée Ligue 2009”, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                3Université Paris 7 Denis Diderot, 10 Avenue de Verdun, 75010 Paris, France
                4Laboratoire M.E.R.C.I, Université de Rouen, 22 Boulevard Gambetta, 76183 Rouen Cedx, France
                5Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France
                6Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France
                7Hôpital Européen Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France
                8Université Descartes-Paris 5, 12 Rue de l'École de Médecine, 75006 Paris, France
                Author notes

                Academic Editor: Fabio Marra

                Copyright © 2010 Annemilaï Tijeras-Raballand et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Research Article

                Gastroenterology & Hepatology


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