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

D Wiederschain, J. Fang, Lijing L. Yan … (2000)

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

D Goeddel, H. M. Rothe, L A Tartaglia … (1993)

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The prothrombotic state in cancer: pathogenic mechanisms.

Marcello De Cicco (2004)

Thrombosis and disseminated intravascular coagulation (DIC) are common complications in cancer. Patients with malignancy have a prothrombotic state due to the ability of almost all type of cancer cells to activate the coagulation system. However, none of the haemostatic markers of coagulation has any predictive value for the occurrence of the thrombotic events in one individual patient. The pathogenesis of the prothrombotic state in cancer is complex and, probably, multifactorial. Prothrombotic factors in malignancy include the tumour production of procoagulants (i.e., tissue factor (TF) and cancer procoagulant (CP)) and inflammatory cytokines, and the interaction between tumour cells and blood (i.e., monocytes/macrophages, platelets) and endothelial cells. Other mechanisms of thrombus promotion include some general responses of the host to the tumour (i.e., acute phase, inflammation, angiogenesis), decreased levels of inhibitors of coagulation, and impaired fibrinolysis. In addition, the prothrombotic tendency of cancer patients is enhanced by anticancer therapy, such as surgery, chemotherapy, hormone therapy and radiotherapy, by indwelling central venous catheter, and by haemodinamic compromise (i.e., stasis). However, not all of the mechanisms allowing the prothrombotic state of cancer are entirely understood. Therefore, it is presently difficult to rank the relative weight of these multiple interactions on the basis of the well-recognised clinical evidences of enhanced thrombotic episodes in patients with cancer. In this review we attempt to describe the current proposed mechanisms for the pathogenesis of the prothrombotic state in cancer patient. A better understanding of these mechanisms could help clinicians in the developments of more targeted treatment to prevent thromboembolic complications in cancer patient.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2008

Publication date (Print): December 2007

Publication date (Electronic): 27 September 2007

Volume: 45

Issue: 1

Pages: 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

Publisher ID: 109079 Other ID: J Vasc Res 2008;45:78–86

DOI: 10.1159/000109079

PubMed ID: 17901709

SO-VID: 36ab1dc8-cbef-4115-b416-d3b7765d0336

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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.

History

Date received : 20 October 2006

Date accepted : 17 June 2007

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Figures: 9, References: 23, Pages: 9

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

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Abstract

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Karger: Cardiovascular System

Most cited references 9

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

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

The prothrombotic state in cancer: pathogenic mechanisms.

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