Table Of ContentExperimental Metastasis: Modeling and Analysis
Anastasia Malek
Editor
Experimental Metastasis:
Modeling and Analysis
1 3
Editor
Anastasia Malek
Oncoendocrinology
Petrov Institute of Oncology
St Petersburg
Russia
ISBN 978-94-007-7834-4 ISBN 978-94-007-7835-1 (eBook)
DOI 10.1007/978-94-007-7835-1
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2013953922
© Springer Science+Business Media Dordrecht 2013
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or
information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts
in connection with reviews or scholarly analysis or material supplied specifically for the purpose of
being entered and executed on a computer system, for exclusive use by the purchaser of the work.
Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright
Law of the Publisher’s location, in its current version, and permission for use must always be obtained
from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance
Center. Violations are liable to prosecution under the respective Copyright Law.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
While the advice and information in this book are believed to be true and accurate at the date of
publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for
any errors or omissions that may be made. The publisher makes no warranty, express or implied, with
respect to the material contained herein.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
Contents
1 Introduction: Experimental Metastasis ................................................... 1
Anastasia Malek
2 Head and Neck Cancer .............................................................................. 7
Mark R. Gilbert, Chwee-Ming Lim and Seungwon Kim
3 Breast Cancer Invasion and Metastasis ................................................... 27
Shane Stecklein, Hanan Elsarraj, Kelli Valdez,
Arindam Paul and Fariba Behbod
4 Mouse Models of Pancreatic Cancer ........................................................ 57
Katherine T. Ostapoff, Michael T. Dellinger, Niranjan Awasthi,
Rolf A. Brekken and Roderich E. Schwarz
5 Brain Metastasis ......................................................................................... 93
Yvonne Kienast
6 Pulmonary Metastasis ............................................................................... 117
Anastasia Malek
7 Liver Metastases ......................................................................................... 141
Ann F. Chambers and Jason L. Townson
8 Malignant Pleural Effusion ....................................................................... 163
Antonia Marazioti and Georgios T. Stathopoulos
9 Mathematical Modeling of the Metastatic Process ................................. 189
Jacob G. Scott, Philip Gerlee, David Basanta, Alexander G. Fletcher,
Philip K. Maini and Alexander R. A. Anderson
Index .................................................................................................................. 209
v
Contributors
Alexander R. A. Anderson Integrated Mathematical Oncology, H. Lee Moffitt
Cancer Center and Research Institute, Tampa, FL, USA
Niranjan Awasthi Department of Surgery, Division of Surgical Oncology, Hamon
Center for Therapeutic Oncology Research, University of Texas, Southwestern,
Dallas, USA
David Basanta Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center
and Research Institute, Tampa, FL, USA
Fariba Behbod Department of Pathology and Laboratory Medicine, The University
of Kansas Medical Center, Kansas City, USA
Rolf A. Brekken Department of Surgery, Division of Surgical Oncology, Hamon
Center for Therapeutic Oncology Research, University of Texas, Southwestern,
Dallas, USA
Department of Pharmacology, Simmons Comprehensive Cancer Center, University
of Texas, Southwestern, Dallas, USA
Ann F. Chambers London Regional Cancer Program and Department of Oncology,
University of Western Ontario, London, Canada
Michael T. Dellinger Hamon Center for Therapeutic Oncology Research,
University of Texas, Southwestern, Dallas, USA
Hanan Elsarraj Department of Pathology and Laboratory Medicine, The
University of Kansas Medical Center, Kansas City, USA
Alexander G. Fletcher Wolfson Centre for Mathematical Biology, Mathematical
Institute, Oxford University, Oxford, UK
Philip Gerlee Mathematical Sciences Division, University of Gothenburg,
Gothenburg, Sweden
Chalmers University of Technology, Gothenburg, Sweden
vii
viii Contributors
Mark R. Gilbert Department of Otolaryngology-Head and Neck Surgery, School
of Medicine, University of Pittsburgh, Pittsburgh, USA
Yvonne Kienast Pharma Research and Early Development, Roche Diagnostics
GmbH, Penzberg, Germany
Seungwon Kim Department of Otolaryngology-Head and Neck Surgery, School
of Medicine, University of Pittsburgh, Pittsburgh, USA
Chwee-Ming Lim Department of Otolaryngology Head and Neck Surgery,
National University Health System Singapore, Singapore, Republic of Singapore
Philip K. Maini Wolfson Centre for Mathematical Biology, Mathematical Institute,
Oxford University, Oxford, UK
Anastasia Malek Department of Oncoendocrinology, Petrov Institute of Oncology,
Sankt-Petersburg, Russia
Antonia Marazioti Department of Physiology, Faculty of Medicine, University of
Patras, Patras, Greece
Katherine T. Ostapoff Department of Surgery, Division of Surgical Oncology,
Hamon Center for Therapeutic Oncology Research, University of Texas,
Southwestern, Dallas, USA
Arindam Paul Department of Pathology and Laboratory Medicine, The University
of Kansas Medical Center, Kansas City, USA
Roderich E. Schwarz IU Health Goshen Center for Cancer Care, Indiana
University School of Medicine, Goshen, USA
Jacob G. Scott Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center
and Research Institute, Tampa, FL, USA
Wolfson Centre for Mathematical Biology, Mathematical Institute, Oxford
University, Oxford, UK
Georgios T. Stathopoulos Department of Physiology, Faculty of Medicine,
University of Patras, Patras, Greece
Shane Stecklein Department of Pathology and Laboratory Medicine, The
University of Kansas Medical Center, Kansas City, USA
Jason L. Townson The University of New Mexico, Center for Micro-Engineered
Materials, Albuquerque, USA
Kelli Valdez Department of Pathology and Laboratory Medicine, The University
of Kansas Medical Center, Kansas City, USA
Chapter 1
Introduction: Experimental Metastasis
Anastasia Malek
Abstract The short introductory chapter is aimed to state importance of the cancer
metastasis research, to review basic approach and to present content and structure
of the book.
1.1 Metastases, the Hallmark of Cancer Disease
Metastatic spread is the most lethal aspect of cancer. The prognosis for cancer
patients is determined by the speed and pattern of metastatic dissemination. For
most tumour types, the diagnosis of metastatic cancer is regarded to indicate a
terminal prognosis, and the effects of metastatic growth are thought to be re-
sponsible for more than 90 % of deaths of cancer patients [1, 2]. In contrast to
therapy for local malignancies, therapeutic approaches to treat advanced cancer
are significantly more variable and aggressive; therapy impacts many vital or-
gans and produces significant side-effects. Currently, for most types of advanced
cancers, therapeutic outcomes are disappointing. This situation induces devel-
opment of palliative care approaches that can improve quality of life, and even
prolong life, for cancer patients [3]. However, complete recovery remains a hope
for all patients.
Intense study of the metastatic process is the only way to improve therapeutic
results for patients with advanced cancer; therefore, it is an essential area of cancer
research. Although development of metastases is a systemic disease process, the
majority of research efforts have focused on understanding the process of local
invasion. Changes in cell adhesion, activation of proteolysis, and the acquisition of
motile properties by tumour cells are accepted as key events in local invasion. Upon
detachment from the primary tumour and entry into the vascular system, survival
of cancer cells is mediated by activation of endogenous morphogenetic processes
such as epithelial-mesenchymal transition and resistance to anoikis. Further spread
of cancer can follow various pathways, which are determined by many known as
well as currently unknown factors.
A. Malek ()
Department of Oncoendocrinology, Petrov Institute of Oncology, Sankt-Petersburg, Russia
e-mail: [email protected]
A. Malek (ed.), Experimental Metastasis: Modeling and Analysis, 1
DOI 10.1007/978-94-007-7835-1_1, © Springer Science+Business Media Dordrecht 2013
2 A. Malek
Lymph node metastases represents the first step in tumor dissemination for
many types of cancer, including head and neck, stomach, pancreas, colon, breast,
cervix, and prostate. The presence of lymph node metastases is a key determinant
in tumor staging, whereas spread of the tumor beyond regional lymph nodes is
traditionally considered as indicator of poor prognosis. However, it is not sim-
ple penetration of lymphatic vessels by cancer cells; rather the lymphatic system
plays an active role in the process of tumor dissemination. A primary tumor is
considered to be capable of modifying the endothelium of adjacent lymph capil-
laries and inducing morphological alteration of lymph nodes even before metas-
tases occur [4]. For instance, specific morphological changes have been observed
in sentinel lymph nodes by growing melanoma. It has been suggested that these
changes are induced by cancer cell–derived exosomes that “prepare” lymph nodes
to accept of disseminating cancer cells [5]. Moreover, it is a well-known fact, that
tumors can stimulate lymphogenesis around and inside the tumor mass. Despite
the fact that intra-tumoural lymphatic vessels are considered to be non-functional,
recent studies have revealed that their density strongly correlates with clinical pa-
rameters of cancers commonly considered to have a tendency for blood-mediated
metastasis (i.e., lung carcinomas, kidney carcinomas, and neuroblastomas [6–8].
Lymph node colonization has been shown to be associated with distant organ
metastasis in a rodent model [9]. As such, the role of the lymphatic system in
cancer dissemination is not limited by implication of regional or distant lymph
nodes; rather, it seems to have a general character. The role of particular molecu-
lar factors and whole regulatory network mediating interaction of tumors with
the lymphatic system have been extensively reviewed [10, 11]. Keeping in mind
the traditional “protective” anti-cancer function of the immune system, its role
as an instigator for distant metastatic dissemination has been discussed in recent
publications [12, 13].
The direction and efficacy of colonization to distant organs by cancer cells
after they have entered the bloodstream is a major issue. In principle, circulat-
ing tumor cells have the potential to access many if not all organs of the body.
Nevertheless, overt metastases do not necessarily form in all organs, and spe-
cific types of tumors exhibit preferential metastasis formation in certain organs.
The lungs, liver, bone, and brain are frequent sites of metastasis formation by
circulating tumor cells. Conversely, metastases virtually never form in skele-
tal muscle, despite its well-developed blood supply. A conceptual framework
to understand these patterns of metastasis is provided by Paget’s seed and soil
hypothesis [14]. Various possible mechanisms may govern or at least simultane-
ously influence cancer dissemination. They include local vasculature structure,
adhesion properties of endothelia, and the tissue environment supporting cancer
cells proliferation. These aspects have been comprehensively reviewed in recent
studies [2]. Investigation of the underlying molecular mechanisms of distant tu-
mor dissemination via the bloodstream may result in new strategies to prevent or
to treat metastatic disease.
1 Introduction: Experimental Metastasis 3
1.2 Modelling Approaches
In order to study and accurately solve the complex interactions between tumor cells
and the whole organism that occurs during metastatic dissemination, it is necessary
to develop and to use appropriate models. It is an obvious fact that any experimen-
tal or computational model may reflect only certain features of the natural process.
There are always factors missing or corrupted by modelling. Consideration of these
aspects is an extremely important issue for conducting experiments, apply models,
and extrapolating results.
In general, the metastatic process may be recapitulated in its entirety with in vivo
models or may be dissected into single steps and assayed in vitro. Both approaches
play essential roles, even considering that their results do not always correlate. Ani-
mal models obviously more closely reflect the actual process in humans; however,
many factors cannot be controlled and may significantly impact the results. The in
vitro approach also has shortcomings; it differs significantly from the actual meta-
static process and can recapitulate only a single aspect of cancer cell vitality (i.e.,
proliferation rate, non-adherent growth ability, motility, invasiveness, and colony
formation activity). Considering the genetic plasticity associated with cancer, tumor
tissue is thought to be polyclonal and contains calls with various genetic alterations
and at various states of proliferative activity. Cell lines established from tumor tis-
sues and cultured in vitro for extended periods of time are established with the goal
of being genetically uniform; however, the cell line may not permanently maintain
the properties of the original tissue. For instance, correlations between the expres-
sion patterns of genes implicated in multi-drug resistance in clinical ovarian cancer
samples and established cell lines have not been observed [15]. All the aspects dif-
fering cell culture experiments from the in vivo situation should be considered. In
order to reduce the impact of in vitro culturing, preclinical studies are often per-
formed using material obtained directly from patients and maintained ex vivo for as
short a time period as possible [16].
Organotypic 3D co-culturing is an experimental approach that is (in terms of
proximity to real situation) in between in vivo and in vitro models. By using various
artificial substances such as Matrigel, Gelfoam, and Collagen Sponge, a three-di-
mensional culture mimicking specific tissue structure can be created. Co-culturing
cancer cells in such a close-to-reality environment can combine the advantages of in
vivo and in vitro methods and provide broad experimental resources.
1.3 The Book Content and Structure
The purpose of this book is to describe recent methodological approaches to can-
cer metastasis research. The focus of this book does not entail either methods of
molecular biology or approaches to the general evaluation of metastatic properties
of cancer cells. The issues regarding the study of the entire metastatic process and
