Table Of ContentTUMOR INVASION AND META ST ASIS
DEVELOPMENTS IN ONCOLOGY 7
Other volumes in this series:
1. F.J. Cleton and J.W.I.M. Simons, eds., Genetic Origins of Tumor Cells
ISBN 90-247-2272-1
2. J. Aisner and P. Chang, eds., Cancer Treatment Research
ISBN 90-247-2358-2
3. B.W. Ongerboer de Visser, D.A. Bosch and W.M.H. van Woerkom-Eykenboom, eds.,
Neuro-Oncology: Clinical and Experimental Aspects
ISBN 90-247-242 I-X
4. K. Hellmann, P. Hilgatd and S. Eccles, eds.,
Metastasis: Clinical and Experimental Aspects
ISBN 90-247-2424-4
5. H.F. Siegler, ed., Clinical Management of Melanoma
ISBN 90-247-2584-4
6. P. Correa, ed., Epidemiology of Cancer of the Digestive Tract
ISBN 90-247-2611-5
Series ISBN: 90-247-2338-8
TUMOR INVASION
AND METASTASIS
edited by
L.A. LIOTTA
National Cancer institute,
Bethesda, Maryland
and
I.R. HART
Frederick Cancer Research Center
Frederick, Maryland
•
1982
MARTINUS NIJHOFF PUBLISHERS
THE HAGUE / BOSTON / LONDON
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Kluwer Boston, Inc.
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jor all other countries
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Library of Congress Cataloging in Publication Data :cJE
Main entry under title:
Tumor invasion and metastasis.
(Developments in oncology; v. 7)
I. Metastasis. 2. Cancer cells. 3. Cell interactions.
1. Liotta, L. A. II. Hart, 1. R. (Ian R.) III. Series. [DNLM: 1. Neoplasm metastasis.
2. Neoplasm invasiveness. WI DE998N v. 7 I QZ 202 T9235]
RC269.T85 616.99'407 81-18967
AACR2
ISBN-13: 978-94-009-7513-2 e-ISBN -13: 978-94-009-7511-8
DOl: 10.1007/978-94-009-7511-8
Copyright © 1982 by Martinus Nijhojj Publishers, The Hague.
Softcover reprint of the hardcover 1s t edition 1982
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system,
or transmitted in any jorm or by any means, mechanical, photocopying, recording, or
otherwise, without the prior written permission of the publishers,
Martinus NijhojfPublishers, P.O. Box 566,2501 CN The Hague, The Netherlands.
Contents
Preface VII
Contributors IX
Section I - Tumor-Host Interactions in Metastasis
1. The role of animal models in the study of experimental metastasis
1.R.HART
2. Eradication of metastases by tumoricidal macrophages: therapeutic
implications 15
1.J. FIDLER
3. The role of natural killer (NK) cells in the control of tumor metastasis 29
N.HANNA
4. Metastasis of xenogeneic and allogeneic tumors in nude mice 43
N.HANNA
5. Cell surface properties of metastatic tumor cells 57
G.L. NICOLSON
6. Metastatic inefficiency 81
L. WEISS
7. Tumor cell chemotaxis 99
J. VARANI and P.A. WARD
8. Antimetastatic concomitant immunity 113
E. GORELIK
9. Immunobiological diversity of metastatic cells 133
E. GORELIK, M. FOGEL, P. DE BAETSELIER, S. KATZAV, M. FELDMAN and
S. SEGAL
Section II - Models of Tumor Invasion
10. Methods and models for studying tumor invasion 147
G. POSTE
11. In vitro quantitative assay of invasion using human amnion 173
R.G. RUSSO, U. THORGEIRSSON and L.A. LIOTTA
12. Experimental models of lymphatic metastasis 189
1. CARR and J. CARR
13. The use of embryo organ cultures to study invasion in vitro 207
M.M.K. MAREEL
14. Three-dimensional models for the study of invasion and metastasis 231
H. GERSHMAN
15. In vitro assay of invasion using endothelial and smooth muscle cells 251
P.A. JONES
16. The regulation of invasion by a cartilage-derived anti-invasion,factor 267
B.U. PAULI and K.E. KUETTNER
Section III - Interaction of Tumor Cells with Connective Tissue
17. Role of cell attachment proteins in defining cell-matrix interactions 291
H.K. KLEINMAN
18. Attachment of metastatic tumor cells to collagen 309
J.C. MURRAY, L.A. LIOTTA and V.P. TERRANOVA
19. Biochemical mechanisms involved in tumor cell penetration of the
basement membrane 319
L.A. LIOTTA, s. GARBISA and K. TRYGGVASON
20. Tumor formation and malignant invasion: role of basal lamina 335
D.E. INGBER and J.D. JAMIESON
21. Plasminogen activator in metastasis 359
J. C. BARRETT and S. SHEELA
22. Proteases in tumor invasion and metastasis 375
R.H. GOLDFARB
23. Collagenase immunolocalisation studies of human tumours 391
D.E. WOOLLEY
24. Host-tumor cell interactions and collagenase activity 405
c. BISWAS
Section IV - Clinical Topics in Metastases
25. Observations on cancer metastasis in man 427
E.V. SUGARBAKER, D.N. WEINGRAD and J.M. ROSEMAN
26. Newer methods for the diagnosis of occult metastases 467
P.S. DICKMAN and T.J. TRICHE
27. Fine needle aspiration cytology of metastases 495
E.W. CHU and S.E. MARTIN
28. Applications ofimmunoperoxidase staining to studies of human breast
disease 511
G.P. SIEGAL and S.H. BARSKY
Index 531
Preface
The clinical significance of tumor spread has always been appreciated. Yet, in spite
of the pioneering work and outstanding contributions of investigators such as D.
Coman, H. Green, B. Fisher, S. Wood and I. Zeidman, studies on metastasis rarely
achieved the popularity afforded to more esoteric areas of tumor biology. Tumor
dissemination, occurring as it does in a responding host and being composed of a
series of dynamic int~ractions, is a highly complex phenomenon. Few investigators
were brave enough to attempt to unravel the mechanisms involved.
Paradoxically, this very complexity may have contributed, in part, to the recent
upsurge of interest in metastasis research. More and more researchers are becoming
fascinated by the complexities of the cellular interactions involved in tumor spread.
Accompanying this intellectual stimulation have been technological advances in
related fields which allow the derivation of new model systems. The mechanisms of
metastatic spread are increasingly amenable to both the reductionist and holistic
approaches and it is the purpose of this volume to present many of these model
systems while emphasizing the intricacy and complexity of the processes they
mimic. We have attempted to emphasize two topics not previously covered in depth
in previous books on metastases. These are in vitro models of invasion and in
teractions of tumor cells with connective tissue.
We believe that the present contributions capture some of the excitement and
drive that presently pervade this area of tumor biology. Any progress toward the
successful achievement of the aims of this book is entirely due to the contributors,
whereas any failures may be ascribed to the editors. Constraints of space prevent
inclusion of much that is undoubtedly important in metastasis research and the
contents of this volume reflect, to a large extent, the personal bias of the editors.
This book can do no more than give a hint of the directions in which research into
the biology of metastasis is moving. Hopefully, these areas are as of much interest to
the reader as they are to the editors.
L.A. Liotta
I.R. Hart
Contributors
BAETSELIER, P. DE, Dienst Algemene Biologie, Vrije Universiteit, Brussels, Belgium.
BARRET, J.C., National Institute of Environmental Health Sciences, P.O. Box 12233, Research
Triangle Park, NC 27709, U.S.A.
BARSKY, S.H., Department of Pathology, National Cancer Institute, National Institutes of Health,
Bethesda, MD 20205, U.S.A.
BISWAS, c., Developmental Biology Laboratory, Massachusetts General Hospital, 32 Fruit Street,
Boston, MA 02114, U.S.A.
CARR, I. and J., Departments of Pathology and Physiology, University of Saskatchewan, Saskatoon,
Saskatchewan, S7N OWO Canada.
CHU, E.W., Head of Cytopathology, National Cancer Institute, Bldg. 10, Rm. 2A19, 9000 Rockville
Pike, Bethesda, MD 20205, U.S.A.
DICKMAN, P., Laboratory of Pathology, National Cancer Institute, Bldg. 10, Rm. 2A27, 9000
Rockville Pike, Bethesda, MD 20205, U.S.A.
FELDMAN, M., The Weizmann Institute of Science, Rehovot, Israel.
FIDLER, I.J., Director, Cancer Metastasis and Treatment Laboratory, Frederick Cancer Research
Center, P.O. Box B, Frederick, MD 21701, U.S.A.
FOGEL, M., Institut fUr Immunologie und Genetik am Deutschen Krebsforschungszentrum, Heidel
berg, Federal Republic of Germany.
GARBISA, S., Institute of Histology and General Embryology, University of Padua, Padua, Italy.
GERSHMAN, H., Department of Biochemistry, Case Western Reserve University, School of Medicine,
2119 Abington Road 14263, Cleveland, OH 44106, U.S.A.
GOLDFARB, R.H., Cancer Metastases Research Group, PfIzer Labs, Central Research, Eastern Point
Road, Groton, CT 06340, U.S.A.
GORELIK, E., Laboratory of Immunodiagnosis, National Cancer Institute, National Institutes of
Health, 9000 Rockville Pike, Bethesda, MD 20205, U.S.A.
HANNA, N., Cancer Metastasis and Treatment Laboratory, National Cancer Institute, Frederick
Cancer Research Center, P.O. Box B, Bldg. 539, Frederick, MD 21701, U.S.A.
HART, I.R., Cancer Metastasis and Treatment Laboratory. National Cancer Institute, Frederick
Cancer Research Center, P.O. Box B, Bldg. 539, Frederick, MD 21701, U.S.A.
INGBER, D.E., Section of Cell Biology, Yale University, School of Medicine, 333 Cedar Street, P.O.
Box 3333, New Haven, CT 06510, U.S.A.
JAMIESON, J.D., Section of Cell Biology, Yale University, School of Medicine, 333 Cedar Street, P.O.
Box 3333, New Haven, CT 06510, U.S.A.
JONES, P.A., Children's Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, U.S.A.
KATZAV , S., The Weismann Institute of Science, Rehovot, Israel.
KLEINMAN, H.K., National Institute of Dental Research, National Institutes of Health, 9000 Rock
ville Pike, Bldg. 30, 4th Floor, Bethesda, MD 20205, U.S.A.
KUETTNER, K.E., Chairman, Professor of Orthopedics and Surgery, Department of Orthopedic
Surgery, Rush-Presbyterian - St. Luke's Medical Center, 1753 West Congress Parkway, Chicago, IL
60612, U.S.A.
LIOTTA, L.A., Laboratory of Pathophysiology, National Cancer Institute, National Institutes of
Health, 9000 Rockville Pike, Bldg. 10, Rm. 5B36, Bethesda, MD 20205, U.S.A.
MAREEL, M.M.K., Academic Hospital, Clinic for Radiotherapy and Nuclear Medicine, Department
of Experimental Cancerology, De Pintelaan 135, B-900 Ghent, Belgium.
MARTIN, S.E. Cytopathology Section, Laboratory ofP athology, National Cancer Institute, Bethesda,
MD 20205, U.S.A.
MURRAY, J.C., Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 4RN, Eng
land.
NICOLSON, G.L., Department of Tumor Biology (108), University of Texas System Cancer Center,
M.D. Anderson Hospital and Tumor Institute, Houston, TX 77030, U.S.A.
PAULI, B.U., Rush Medical College, 1753 West Congress Parkway, Chicago, IL 60612, U.S.A.
POSTE, G., Vice President and Director of Research, Smith, Kline and French Laboratories, 1500
Spring Garden Street, P.O. Box 7929, Philadelphia, PA 19101, U.S.A.
ROSEMAN, J.M., 1399 S.W. First Avenue, Miami, FL 33131, U.S.A.
RUSSO, R.G" Laboratory of Pathophysiology, National Cancer Institute, Bldg. 10, 8-19, National
Institutes of Health, Bethesda, MD 20205, U.S.A.
SEGAL, S., The Weizmann Institute of Science, Rehovot, Israel.
SHEELA, S., National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle
Park, NC 27709, U.S.A.
SIEGAL, G.P., Department of Laboratory Medicine and Pathology, University of Minnesota, Minnea
polis, MN 55455, U.S.A.
SUGARBAKER, E.V., 1399 SW. First Avenue, 200 B, Miami, FL 33131, U.S.A.
TERRANOVA, V.P., National Institute of Dental Research, National Institutes of Health, Bldg. 30, 4th
Floor, 9000 Rockville Pike, Bethesda, MD 20205, U.S.A.
THORGEIRSSON, U., Laboratory of Pathophysiology and Pathology, National Cancer Institute,
National Institutes of Health, Bethesda, MD 20205, U.S.A.
TRICHE, TJ., Laboratory of Pathology, National Cancer Institute, Bldg. 10, Rm. 2A27, 9000 Rock
ville Pike, Bethesda, MD 20205, U.S.A.
TRYGGVA SON, K., Department of Clinical Chemistry and Medical Biochemistry, University ofOulu,
Finland.
VARANI, J., Department ofP athology, University of Michigan, School of Medicine, 1335 E. Catherine
Street, Ann Arbor, MI 48109, U.S.A.
WARD, P.A., Department of Pathology, University of Michigan, School of Medicine, 1335 E. Ca
therine Street, Ann Arbor, MI 48109, U.S.A.
WEINGRAD, D.N., 1399 S.W. First Avenue, Miami, FL. 33131, U.S.A.
WEISS, L., Director of Cancer Research, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY
14263, U.S.A.
WOOLLEY D.E., University Department of Medicine, University Hospital of South Manchester, Nell
Lane, West Didsbury, Manchester M20 8LR, England.
1. The role of animal models in the study of experimental
metastasis 1
I.R. HART
1. Introduction
Metastasis is a dynamic process that occurs in vivo and, therefore, studies of cancer
metastasis must logically include data from in vivo experiments and observations.
Failure to consider these in vivo data can result in the investigation of irrelevant,
albeit fascinating, epiphenomena of in vitro systems. Identification of the tumor cell
or host characteristics that are important for metastatic dissemination can only be
made when there are strong correlations between possession of, or alterations in, the
observed phenotype and changes in the in vivo behavior of that tumor in the
appropriate host. All too often investigators have proposed that particular alter
ations or modifications in cellular properties are responsible for differences in
metastatic behavior without first verifying that the cells under investigation were
indeed capable of metastasis [1].
Correlations between various cellular properties and metastatic behavior may be
obtained by comparing data to historical clinical observations, as is necessary when
cells from autochthonous tumors of man or domestic animals are used in in vitro
assays. However, scientists often use a variety of transplantable tumors in labo
ratory animals to investigate the process of metastasis. In this chapter, we review
some of the salient features of these tumor models and indicate some advantages
and limitations.
Stedman's Medical Dictionary [2] defines a model as 'A representation of some
thing, usually idealized and modified to make it conceptually easier to understand.'
Although this modification towards simplicity is an obvious advantage, it may,
paradoxically, constitute the greatest disadvantage of a model, since simplicity
frequently is obtained only at the expense of clinical relevance. More will be said in
the following section regarding the advisability of extrapolating from results de
rived from model systems to produce generalizations of apparent clinical signific
ance. It is sufficient to state at this point that to restrict the use of models to only
those that exactly resemble the clinical situation is to impose precisely those con-
1 Research sponsored by the National Cancer Institute, DHHS, under Contract No. NOl-CO-75380
with Litton Bionetids, Inc. The contents ofthis publication do not necessarily reflect the views or policies
of the Department of Health and Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
L.A. Liotta and I.R. Hart (eds.), Tumor Invasion and Metastasis. ISBN-J3:978-94-009-75J3-2
© 1982 Martinus Nijhoff Publishers, The Hague/Boston/London.
