Inflammation and Metastasis

951 Pages·2016·8.07 MB·English

by  Yoshiro Maru

Yoshiro Maru
Inflammation and Metastasis
Yoshiro Maru
Department of Pharmacology, Tokyo Women’s Medical
University, Tokyo, Japan
ISBN 978-4-431-56022-7 e-ISBN 978-4-431-56024-1
DOI 10.1007/978-4-431-56024-1
Library of Congress Control Number: 2016934318
© Springer Japan 2016
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This book is dedicated to my wife
Preface
In this book, I attempt to describe a way for readers to
contemplate how to approach the complicated issue of
inflammation and tumor progression.
As of January 30, 2015, the precision medicine initiative by
President Obama was manifested [1]. My understanding is that
one of the objectives would be elucidation of complex
mechanisms underlying human diseases by integrating
environmental factors. Understanding cancer metastasis by
inflammation that is caused by both environmental and
endogenous elements is one such issue described in this book. A
more precise classification of disease into subgroups as
discussed by advisory board members may correspond to
distinction between prometastatic and nonmetastatic subgroup of
a given tumor and patient [2].
Summarizing what is written in the literature without
including his own ideas often results in an ambiguous table of
lists showing the names of molecules based on publication
without interpretations. I was an active professor of more than
10 years before official retirement and still struggle to cope with
experimental difficulties. Originally, I am a physician specialized
in hematology and started my research on oncogenes and human
leukemia in 1985. I obtained my thesis on the discovery of Eph
tyrosine kinase in 1987. After spending a postdoctoral career at
UCLA under Dr. Owen N. Witte from 1989 through 1993
working on the BCR-ABL oncogene of chronic myeloid leukemia
(CML), I began my research on angiogenesis at the University of
Tokyo with Dr. Masabumi Shibuya. By particularly focusing on
VEGF receptor 1, I also learned about extracellular matrix and its
interacting molecules, such as proteases. Since I became a chair
of the Department of Pharmacology at Tokyo Women’s Medical
University in 2002, I can afford to continue my research on CML,
Eph, and VEGF. This has made my research background of
leukocyte, tumor biology, and angiogenesis. Since 2004, I have
been focused on tumor metastasis in collaboration with
researchers of innate immunology. Thus, I would like to underline
that I challenge the big issue of metastasis by still working on and
combining the experimental experience of tumor biology,
angiogenesis, and immune system from both clinical and basic
standpoints. This book was not designed to collect all of the
information on inflammation, tumor, immune system, and
infection. It is just impossible, and I apologize to those whose
excellent work I was unable to cite simply because of space.
Some of the milestone reviews of excellence are as follows.
The tumor biology started with discoveries of oncogenes and
tumor-suppressor genes in the research background of tumor
development in animals and cell transformation, particularly from
the standpoint of cell proliferation [3]. In the course of the
progress, pleiotropic activities of tumor suppressors were nicely
described by Sherr, including not only mitogenic signaling but
also cell-cycle checkpoint, DNA repair, and protein stability [4].
In 2011, Hanahan and Weinberg described eight hallmarks of
cancer, i.e., sustained growth, evasion of growth suppressors,
resisting cell death, replicative immortality, tumor angiogenesis,
metastasis, genetic instability, inflammation, metabolic
reprogramming, and immune alteration [5]. Among those,
Massague focused on the most life-threatening feature: metastasis
[6]. He and his colleagues described how infiltrating cancer cells
as seed need to cope with deadly soil as metastatic
microenvironment. One such way is to acquire what they called
metastatic traits, such as mutations and alteration of expression
levels of responsible genes in metastatic tumor cells.
Currently, we cannot understand cancer without knowledge of
inflammation (Part III and Part IV). Inflammation and cancer is
just like the chicken and egg. In 2001, inflammatory responses to
cancer were introduced and blockade of inflammatory cytokines
and chemokines was proposed for cancer treatments by Balkwill
and Mantovani [7]. They described in Cancer Cell in 2005 that
polarized macrophages and persistent inflammation underlie in
cancer [8] and in Nature in 2008 how oncogenes induce
inflammation by referring to expression of cytokines-chemokines
and their receptors [9]. Also in 2002, Coussens described wound
healing as an example of what they called physiological
inflammation [10]. Cancer-associated inflammation was
proposed to give an opportunity for therapy. The concept of
physiological inflammation is closely linked to what Matzinger
proposed in 2002 as danger hypothesis [11]. The idea that the
immune system is concerned with danger but not non-self was
proposed by Matzinger back in 1994. Although she described
dangerous self and harmless foreign, tumors are recognized as
neither associated with microbial stimulators nor able to send
alarm signals. Endogenous alarmins, i.e., tumor-derived
transformed and therefore dangerous selfs were not stated (Part
II).
In 2008, Medzhitov reported endogenous inducers of
inflammation, such as uric acid, S100A8, and HMGB1 [12]. An
idea called para-inflammation also was proposed in which
leukocytes help a tissue to adapt to stress for its restoration.
Takeuchi and Akira focused on pattern recognition receptors for
microbe-derived exogenous ligands, in which they did not
include receptors, such as PTX3, CRP, and CD36 [13]. An idea
of endogenous ligands or danger-associated molecular patter
(DAMP) was described by Karin [14]. The paper reported the
bidirectional signaling between immune and tumor cells.
Inflammation has both pro- and antitumorigenic effects, the
balance of which may determine the fate. Protumorigenic
activities often are under vicious cycle with NFκB, which is
involved from tumor development to metastasis. They discussed
DAMP derived from surgery, chemotherapy, and irradiation
against tumors. For therapeutic standpoint, Dinarello summarized
anti-inflammatory agents but without any particular focus on
given diseases [15].
The idea of premetastasis cannot be explained by danger
hypothesis simply because premetastatic microenvironment is a
condition without tissue destruction and before arrival of true
danger as tumor cells and may include still reversible periods of
para-inflammation (Part IV). The whole spectrum, including
physiological inflammation, which is homeostatic and reversible,
para-inflammation and danger-induced inflammation is proposed
as homeostatic inflammation [16, 17].
References

1. Press Secretary. Fact sheet: President Obama’s Precision
Medicine Initiative (The White House, Office of the Press
Secretary, 30 January 2015). 2015. https:// www.
whitehouse. gov/ the-press-office/ 2015/ 01/ 30/ fact-
sheet-president-obama-s-precision-medicine-initiative .

2. Katsnelson A. Momentum grows to make “personalized”
medicine more “precise.” Nat Med. 2013;19:249.

3. Bishop JM. Molecular themes in oncogenesis. Cell.
1991;64:235–48.

4. Sherr CJ. Principles of tumor suppression. Cell.
2004;116:235–46.

5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next
generation. Cell. 2011;144:646–74.

6. Vanharanta S, Massague J. Origins of metastatic traits.
Cancer Cell. 2013;24:410–21.

7. Balkwill F, Mantovani A. Inflammation and cancer: back to
Virchow? Lancet. 2001;357:539–45.

8. Balkwill F, Charles KA, Mantovani A. Smoldering and
polarized inflammation in the initiation and promotion of
malignant disease. Cancer Cell. 2005;7:211–17.

9. Mantovani A, Allavena P, Sica A, et al. Cancer-related
inflammation. Nature. 2008;454:436–44.