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      Phenotypic and Functional Differences between Human Liver Cancer Endothelial Cells and Liver Sinusoidal Endothelial Cells

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          Abstract

          Background/Aims: The phenotypic and functional characteristics of microvascular endothelial cells derived from human liver cancer (HLCEC) were analyzed in vitro and compared with those of human liver sinusoidal endothelial cells (LSEC). Methods and Results: Flow-cytometric and real-time PCR analysis indicated that expressions of tumor necrosis factor receptor (TNFR) p75, αvβ3 and αvβ5 were increased, while those of TNFR p55 and intercellular-adhesion molecule 1 (ICAM-1) were decreased in HLCEC compared with LSEC. The functional analysis indicated that HLCEC exhibited higher angiogenic ability than LSEC, including proliferation capacity, ability to form capillary-like networks and release of matrix metalloproteinases. In response to tumor necrosis factor, LSEC exhibited a significant dose-dependent cytotoxicity, while HLCEC did not. Moreover, the coagulant and fibrinolytic capacity was increased in HLCEC. In addition, tumor cell adherence was significantly higher on HLCEC than on LSEC, while leukocyte adherence was lower on HLCEC than on LSEC. The cytoadherence of HLCEC was inhibited by antibodies against αvβ3 and αvβ5,and of LSEC by antibodies against ICAM-1. Conclusion: These results indicate that tumor-derived endothelial cells are phenotypically and functionally different from those derived from normal liver tissue. These differences are valuable for understanding tumor angiogenesis and metastasis.

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          Most cited references 9

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          Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor.

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            Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model.

            Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the "switch to the angiogenic phenotype." We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro. In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro. Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro. Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype.
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              Is Open Access

              Reversible immortalization of human primary cells by lentivector-mediated transfer of specific genes.

              We exploited the ability of lentiviral vectors to govern the stable transduction of cells irrespective of their cycling status to induce the reversible immortalization of human primary cells. First, bicistronic HIV-derived lentiviral vectors expressing GFP- and the HSV1 thymidine kinase and containing the LoxP sequence in their LTR (HLox) were used to transduce HeLa cells. Cre expression led to efficient proviral deletion, and unexcised cells could be eliminated by ganciclovir treatment. A human liver biopsy was then exposed to a combination of HLox vectors that harbored either the SV40 large T (TAg) or the human telomerase (hTERT) DNAs in place of GFP. This led to the isolation of liver sinusoidal endothelial cell (LSEC) clones that exhibited an immortalized phenotype while retaining most of the features of primary hLSEC. Complete growth arrest of these cells was observed in 2 days of Cre expression, and the resulting stationary culture could be kept for at least 2 weeks. Transduction of human adult pancreatic islets with HLox vectors coding for Tag and Bmi-1 also induced the proliferation of insulin-positive cells. These results indicate that lentivectors can be used to mediate the reversible immortalization of primary nondividing cells and should allow for the production of large supplies of a wide variety of human cells for both therapeutic and research purposes.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2008
                December 2007
                27 September 2007
                : 45
                : 1
                : 78-86
                Affiliations
                aInstitute of Clinical Medical Sciences, China-Japan Friendship Hospital, bInstitute of Basic Medical Sciences, Beijing Union Medical College, and cCancer Institute (Hospital), Chinese Academy of Medical Sciences, Beijing, PR China; dDepartment of Pathology, K25, Faculty of Medicine, University of Sydney, Sydney, Australia
                Article
                109079 J Vasc Res 2008;45:78–86
                10.1159/000109079
                17901709
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 9, References: 23, Pages: 9
                Categories
                Research Paper

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