The Link Between Inflammation and Cancer - Wounds That Do Not Heal

260 Pages·2006·16.517 MB·English

by  A. Dalgleish, B. Haefner

THE LINK BETWEEN
INFLAMMATION AND CANCER
Wounds that do not heal
Cancer Treatment and Research
Steven T. Rosen, M.D., Series Editor
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THE LINK BETWEEN
INFLAMMATION AND CANCER
Wounds that do not heal
edited by
ANGUS G. DALGLEISH, MD
Division of Oncology
St George's Hospital Medical School
London, UK
BURKHARD HAEFNER, PhD
Department of Oncology
Johnson & Johnson Pharmaceutical
Research and Development
BeersCy Belgium
Sprrii nger
Burkhard Haefner, PhD Angus G. Dalgleish, MD
Department of Oncology Division of Oncology
Johnson and Johnson Pharmaceutical St. George’s Hospital Medical School
Research and Development Cranmer Terrace
Turnhoutseweg 30, Box 6423 London SW17 0RE, United Kingdom
2340 Beerse, Belgium
THE LINK BETWEEN INFLAMMATION AND CANCER
Wounds that do not heal
Library of Congress Control Number: 2005934590
ISBN-10: 0-387-26282-2 e-ISBN-10: 0-387-26283-0
ISBN-13: 978-0387-26282-6 e-ISBN-13: 978-0387-26283-3
Printed on acid-free paper.
(cid:164) 2006 Springer Science+Business Media, Inc.
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CONTENTS
Foreword vii
Angus G. Dalgleish and Burkhard Haefner
Contributors xi
1. Inflammation and Cancer: The role of the immune 1
response and angiogenesis
Angus G. Dalgleish and Ken O'Byme
2. Chronic Inflammation and Pathogenesis of GI and 39
Pancreatic Cancers
Lindsey N. Jackson and B. Mark Evers
3. Cytokines, NF-KB, Microenvironment, Intestinal 67
Inflammation and Cancer
Amdt J. Schottelius and Harald Dinter
4. Regulation of NF-KB Transcriptional Activity 89
Linda Vermeulen, Wim Vanden Berghe and Guy Haegeman
5. The Role of Immune Cells in the Tumor 103
Microenvironment
Theresa L. Whiteside
6. Tumor-Microenvironment Interactions: The Selectin- 125
Selectin Ligand Axis in Tumor-Endothelium Cross Talk
Isaac P. Witz
7. CD95L/FasL and Trail in Tumour Surveillance and 141
Cancer Therapy
Harald Wajant
8. Infection & Neoplastic Growth 101: The required reading 167
for microbial pathogens aspiring to cause cancer
Jessica Bertout and Andrei Thomas-Tikhonenko
9. Cytokines as Mediators and Targets for Cancer Cachexia 199
Josep M, Argiles, Silvia Busquets and
Francisco J. Lopez-Soriano
10. Targeting NF-KB in Anticancer Adjunctive
Chemotherapy 219
Burkhard Haefner
Index 247
FOREWORD
A link between inflammation and cancer has been established
many years ago, yet it is only recently that the potential significance
of this connection has become apparent. Although several examples of
chronic inflammatory conditions, often induced by persistent irritation
and/or infection, developing into cancer have been known for some
time, there has been a notable resistance to contemplate the possibility
that this association may apply in a causative way to other cancers.
Examples for such progression from chronic inflammation to cancer
are colon carcinoma developing with increased frequency in patients
with ulcerative colitis, and the increased incidence of bladder cancer
in patients suffering from chronic Schistosoma infection.
Inflammation and cancer have been recognized to be linked in another
context for many years, i.e., with regards to pathologies resembling
chronic lacerations or 'wounds that do not heal.' More recently, the
immunology of wound healing has given us clues as to the
mechanistic link between inflammation and cancer, in as much as
wounds and chronic inflammation turn off local cell-mediated
immune responses and switch on growth factor release as well the
growth of new blood vessels - angiogenesis. Both of these are
features of most types of tumours, which suggest that tumours may
require an immunologically shielded milieu and a growth factor-rich
environment.
The discovery that some cancers are associated with viral
infections and that these viruses only cause cancer in a small
percentage of infected individuals has served to highlight that these
'oncogenic' viruses are extremely 'mild' with regard to the time it
takes to induce cancer and that other factors must be involved.
Examples of these viruses include human papilloma viruses (HPV),
Epstein Barr Virus (EBV) and the two hepatitis viruses, HBV and
HCV. HPV causes cervical cancer in only a small percentage of
infected women, most of whom eventually become clear of infection.
Chronic infection with HPV would appear to be more likely in the
presence of additional infectious agents leading to established
infection and chronic cervicitis. EBV only rarely causes cancer in
Vlll
Western populations, but where it is clearly linked with cancers in a
causative sense, e.g. Burkitt's Lymphoma (BL) in Africa and
nasopharyngeal carcinoma (NPC) in China, there are other chronic co-
factors involved. In the case of BL, there is a strong link to malaria
and with NPC, salted fish acting as an irritant/carcinogen is required.
However, HBV (and HCV) infection, over decades, will induce
chronic hepatitis which evolves into cirrhotic changes from which
hepatomas develop. Although co-factors may be involved, they do not
appear necessary. These examples emphasize that these are extremely
weak oncogenic viruses contained for years by an effective immune
response (the only clear link between EBV and tumours (lymphomas)
in the West are seen in immunosuppressed patients and the tumours
often resolve upon reversal of immunosuppression). The bottom line
is that all these viruses usually only cause malignant transformation
after many years of inflammatory infection.
The rapid growth in our understanding of molecular signaling
pathways in the past decades has taught us that some of these
regulatory cascades appear to be key to the development of cancer
from chronic inflammatory conditions. Pivotal among these signaling
circuits appears to be the NF-KB pathway, crucial for the regulation of
immune and inflammatory responses, and linked to non-inflammatory
core pathways in oncogenesis, such as the p53 pathway. A major
focus of this book, therefore, is the NF-KB pathway as well as the
interaction between the tumour and its microenvironment involving
the immune response, apoptotic pathways, cytokines and the selectins.
In this volume we have tried to highlight the complexity of these
processes, yet at the same time show just how fundamental the basic
link is. Inevitably this means looking at the same scene from different
angles, and hence, there is some degree of overlap. However, the
detail is so impressive that we feel this helps enforce the clarity of the
overall picture, which only goes to raise the question: 'Why has the
link been denied for so long?' The major impact of this book,
however, should be to emphasize the obvious dramatic therapeutic
and preventative implications. Chronic viral infections, for example,
can be vaccinated against. For instance, the widespread availability of
a HBV vaccine for several decades has greatly reduced the incidence
of hepatoma and, as such, can claim to be the first effective
preventative cancer vaccine. The common 'non-infection'-related
tumours such as colon, lung, breast, and prostate cancer, may be
'preventable' by regular administration of anti-inflammatories such as
IX
aspirin. More specific drugs may be derived from studies included in
this book which will lead to more effective preventative strategies as
well as treatments. The link between an inflammatory environment
and more rapid progression has been recognized for a number of
tumours, including breast cancer, clearly suggesting that anti
inflammatory agents may have a major role in therapy. Unfortunately,
several studies using the new COX-2 inhibitors have had to be halted
because of the association with increased heart attack risk. Aspirin of
course is a COX inhibitor which protects against heart attacks and is
an obvious candidate. Unfortunately, gastritis and increased gastric
bleeding tendency have reduced enthusiasm for such studies even
though aspirin has been reported to be preventative for a number of
solid tumours, including breast cancer as well as colorectal cancer.
Clearly, there still is ptenty of scope for the development of improved
anti-inflammatory drugs which can be used in cancer prevention as
well as treatment.
The recognition of the link with chronic inflammation allows
for new ways of understanding how cancers progress and how
different types of cancer can show similar responsiveness to drug
treatment, which is already being seen for Avastin, a monoclonal
antibody which targets vascular endothelial growth factor and is active
in disparate tumour types. Another example of how this approach can
influence cancer treatment is Revlimid, a Thalidomide analogue
developed by Celgene. It was selected for its anti-TNF and thus anti
inflammatory activity but was found to also have strong anti-
angiogenic properties and to stimulate the cell-mediated immune
response. This compound may thus deliver an ideal three-way blow to
tumours and has recently been shown to be highly active against
multiple myeloma. It would be surprising if it did not act against other
tumour types as well. Thus, we feel confident in proclaiming that this
book does not merely cover a speculative theory, but rather the basis
for a therapeutical revolution in the treatment of cancer.
Angus G, Dalgleish, MD
Burkhard Haefner, PhD