Inflammation and Cancer

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Editors
Bharat B. Aggarwal
Bokyung Sung
Subash Chandra Gupta
Department of Experimental Therapeutics
The University of Texas M.D. Anderson
Cancer Center
Houston, TX
USA

ISSN 0065-2598 ISSN 2214-8019 (electronic)

ISBN 978-3-0348-0836-1 ISBN 978-3-0348-0837-8 (eBook)
DOI 10.1007/978-3-0348-0837-8
Springer Basel Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014937690

© Springer Basel 2014

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Preface

It was Aulus Cornelius Celsus, a physician in first-century Rome, who first defined
inflammation as calor (heat), dolor (pain), rubor (redness), and tumor (swell-
ing). However, it was Rudolf Virchow who in the mid-1800s linked inflammation
with atherosclerosis, rheumatoid arthritis, multiple sclerosis, asthma, Alzheimer’s
disease, cancer, and other chronic diseases. The suffix “-itis” was introduced to indi-
cate inflammation in words such as bronchitis (inflammation of the bronchus) and
colitis (inflammation of the colon). Extensive research has revealed that inflam-
mation precedes most cancers; for example, cancers of the liver, lung, colon,
cervix, pancreas, stomach, and prostate are preceded by hepatitis, bronchitis,
colitis, cervicitis, pancreatitis, gastritis, and prostatitis, respectively.
Within the past three decades, researchers have determined the molecular basis
of most kinds of inflammation. Furthermore, various cell-signaling pathways
that lead to inflammation have also been relatively well defined, leading to the
development of various therapeutics that can modulate these pathways and thus
alter the course of disease.
The current monograph deals with the role of inflammation in cancer, and some
of the leaders in the field have contributed to this volume. We would like to thank
these experts for their contributions and the publisher for giving us the opportunity
to edit this volume.

Bharat B. Aggarwal
Bokyung Sung
Subash Chandra Gupta

v
Contents

1 The Role of Inflammation in Lung Cancer. . . . . . . . . . . . . . . . . . . . . . . 1

Mónica Gomes, Ana Luísa Teixeira, Ana Coelho, António Araújo
and Rui Medeiros

2 The Role of Inflammation in Colon Cancer. . . . . . . . . . . . . . . . . . . . . . 25

Naveena B. Janakiram and Chinthalapally V. Rao

3 The Role of Inflammation in Inflammatory Breast Cancer . . . . . . . . . 53

Tamer M. Fouad, Takahiro Kogawa, James M. Reuben
and Naoto T. Ueno

4 The Role of Inflammation in Brain Cancer . . . . . . . . . . . . . . . . . . . . . . 75

James L. Sowers, Kenneth M. Johnson, Charles Conrad,
Joel T. Patterson and Lawrence C. Sowers

5 The Role of Inflammation in Head and Neck Cancer. . . . . . . . . . . . . . 107

Marcelo Bonomi, Alexis Patsias, Marshall Posner
and Andrew Sikora

6 The Role of Inflammation in Pancreatic Cancer. . . . . . . . . . . . . . . . . . 129

Simone Hausmann, Bo Kong, Christoph Michalski, Mert Erkan
and Helmut Friess

7 The Role of Inflammation in Prostate Cancer. . . . . . . . . . . . . . . . . . . . 153

Karen S. Sfanos, Heidi A. Hempel and Angelo M. De Marzo

8 The Role of Inflammation in Bladder Cancer . . . . . . . . . . . . . . . . . . . . 183

Georgios Gakis

9 The Role of Inflammation in Kidney Cancer. . . . . . . . . . . . . . . . . . . . . 197

Antonio Roma de Vivar Chevez, James Finke and Ronald Bukowski

vii
viii Contents

Kazım Şenol, Murat Bulut Özkan, Selahattin Vural and Mesut Tez
10 The Role of Inflammation in Gastric Cancer. . . . . . . . . . . . . . . . . . . . 235

11 The Role of Inflammation in Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . 259

Jürgen Radons

12 The Role of Inflammation in Lymphoma. . . . . . . . . . . . . . . . . . . . . . . 315

Antonino Carbone, Claudio Tripodo, Carmelo Carlo-Stella,
Armando Santoro and Annunziata Gloghini

13 The Role of Inflammation in Leukaemia . . . . . . . . . . . . . . . . . . . . . . . 335

Francis J Giles, Janusz Krawczyk, Michael O’Dwyer,
Ronan Swords and Ciara Freeman

14 The Role of Inflammatory Cells in Angiogenesis in

Multiple Myeloma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Domenico Ribatti and Angelo Vacca

15 The Role of Inflammation in Cervical Cancer. . . . . . . . . . . . . . . . . . . 377

S. Deivendran, K. Hezlin Marzook and M. Radhakrishna Pillai

16 The Role of Inflammation in Liver Cancer . . . . . . . . . . . . . . . . . . . . . 401

Anupam Bishayee

17 The Role of Inflammation in Skin Cancer. . . . . . . . . . . . . . . . . . . . . . 437

Girish B. Maru, Khushboo Gandhi, Asha Ramchandani and
Gaurav Kumar

Editors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Contributors

António Araújo Chief of the Medical Oncology Service of Centro Hospitalar do

Porto, Porto, Portugal; Chief of the Medical Oncology Service of Centro H
­ ospitalar
de Entre Douro e Vouga, Santa Maria da Feira, Portugal; Instituto de Ciências
­Biomédicas de Abel Salazar, Porto, Portugal
Anupam Bishayee Department of Pharmaceutical Sciences, School of Pharmacy,
American University of Health Sciences, Signal Hill, CA, USA
Marcelo Bonomi Head and Neck Oncology Program, Wake Forest School of Med-
icine, Winston-Salem, NC, USA
Ronald Bukowski Cleveland Clinic Lerner College of Medicine, Case Western
Reserve University, Cleveland, OH, USA
Antonino Carbone Department of Pathology, Centro di Riferimento Oncologico
Aviano, Istituto Nazionale Tumori, IRCCS, Aviano, Italy
Carmelo Carlo-Stella Department of Oncology and Hematology, Humanitas
­Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
Ana Coelho Instituto Português de Oncologia do Porto Francisco Gentil, EPE,
Grupo de Oncologia Molecular—CI, Porto, Portugal; Faculty of Medicine of
University of Porto, Porto, Portugal; LPCC Research Department-Portuguese
­
League Against Cancer (NRNorte), Porto, Portugal
Charles Conrad Department of Neuro-Oncology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Angelo M. De Marzo Department of Pathology, The Johns Hopkins University
School of Medicine, Baltimore, MD, USA
Antonio Roma de Vivar Chevez Cleveland Clinic Lerner College of Medicine,
Case Western Reserve University, Cleveland, OH, USA
S. Deivendran Cancer Research Program, Rajiv Gandhi Centre for Biotechnology,
Thiruvananthapuram, India
Mert Erkan Department of Surgery, Klinikum rechts der Isar, Technische
­Universität München, Munich, Germany

ix
x Contributors

James Finke Cleveland Clinic Lerner College of Medicine, Case Western Reserve
University, Cleveland, OH, USA
Tamer M. Fouad Department of Breast Medical Oncology, Morgan Welch
Inflammatory Breast Cancer Research Program and Clinic, The University of
­
Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medical
­Oncology, The National Cancer Institute, Cairo University, Cairo, Egypt
Ciara Freeman Department of Haematology, Barts and the Royal London NHS
Trust, London, UK
Helmut Friess Department of Surgery, Klinikum rechts der Isar, Technische
­Universität München, Munich, Germany
Georgios Gakis Department of Urology, University Hospital Tübingen,
­Eberhard-Karls University, Tübingen, Germany
Khushboo Gandhi Maru Lab, Advanced Centre for Treatment, Research and
­Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi
Mumbai, India
Francis J Giles Northwestern Medicine Developmental Therapeutics ­Institute,
Robert H. Lurie Comprehensive Cancer Center of Northwestern University,
­Chicago, USA
Annunziata Gloghini Department of Diagnostic Pathology and Laboratory
­Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Mónica Gomes Instituto Português de Oncologia do Porto Francisco Gentil, EPE,
Grupo de Oncologia Molecular—CI, Porto, Portugal; ICBAS, Abel Salazar I­ nstitute
for the Biomedical Sciences, University of Porto, Porto, Portugal; LPCC Research
Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal
Simone Hausmann Department of Surgery, Klinikum rechts der Isar, Technische
Universität München, Munich, Germany
Heidi A. Hempel Department of Pathology, The Johns Hopkins University School
of Medicine, Baltimore, MD, USA
Naveena B. Janakiram Center for Cancer Prevention and Drug Development,
Department of Medicine, Hematology Oncology Section, PCS Cancer Center,
­University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
Kenneth M. Johnson Department of Pharmacology and Toxicology, The
­University of Texas Medical Branch (UTMB), Galveston, TX, USA
Takahiro Kogawa Department of Breast Medical Oncology, Morgan Welch
­Inflammatory Breast Cancer Research Program and Clinic, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Bo Kong Department of Surgery, Klinikum rechts der Isar, Technische Universität
München, Munich, Germany
Contributors xi

Janusz Krawczyk Department of Haematology, Galway University Hospital,

­Galway, Ireland
Gaurav Kumar Maru Lab, Advanced Centre for Treatment, Research and
­Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi
Mumbai, India
Girish B. Maru Maru Lab, Advanced Centre for Treatment, Research and
­Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi
Mumbai, India
K. Hezlin Marzook Cancer Research Program, Rajiv Gandhi Centre for
­Biotechnology, Thiruvananthapuram, India
Rui Medeiros Instituto Português de Oncologia do Porto Francisco Gentil, EPE,
Grupo de Oncologia Molecular—CI, Porto, Portugal; ICBAS, Abel Salazar I­ nstitute
for the Biomedical Sciences, University of Porto, Porto, Portugal; LPCC Research
Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal;
CEBIMED, Health Sciences Faculty, Fernando Pessoa, University of Porto, Porto,
­Portugal
Christoph Michalski Department of Surgery, Klinikum rechts der Isar, ­Technische
Universität München, Munich, Germany
Michael O’Dwyer Biosciences, National University of Ireland Galway, Galway,
Ireland
Murat Bulut Özkan Department of General Surgery, Ankara Numune Research
and Training Hospital, Ankara, Turkey
Alexis Patsias Head and Neck Oncology Program, Mount Sinai School of
­Medicine, New York, USA
Joel T. Patterson Department of Surgery, Division of Neurosurgery, UTMB,
­Galveston, TX, USA
Marshall Posner Head and Neck Oncology Program, Mount Sinai School of
­Medicine, New York, USA
M. Radhakrishna Pillai Cancer Research Program, Rajiv Gandhi Centre for
­Biotechnology, Thiruvananthapuram, India
Jürgen Radons Department of Radiotherapy and Radiation Oncology, Klinikum
rechts der Isar, Technische Universität München, Munich, Germany
Asha Ramchandani Maru Lab, Advanced Centre for Treatment, Research and
Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi
Mumbai, India
Chinthalapally V. Rao Center for Cancer Prevention and Drug Development,
­Department of Medicine, Hematology Oncology Section, PCS Cancer Center,
­University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
xii Contributors

James M. Reuben Department of Hematopathology, Morgan Welch Inflammatory

Breast Cancer Research Program and Clinic, The University of Texas MD Anderson
Cancer Center, Houston, TX, USA
Domenico Ribatti Department of Basic Medical Sciences, Neurosciences and
Sensory Organs, Section of Human Anatomy and Histology, University of Bari
Medical School, Bari, Italy; National Cancer Institute, Bari, Italy
Armando Santoro Department of Oncology and Hematology, Humanitas Cancer
Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
Kazım Şenol Department of General Surgery, Ankara Numune Research and
­Training Hospital, Ankara, Turkey
Karen S. Sfanos Department of Pathology, The Johns Hopkins University School
of Medicine, Baltimore, MD, USA
Andrew Sikora Head and Neck Oncology Program, Mount Sinai School of
­Medicine, New York, USA
James L. Sowers Department of Pharmacology and Toxicology, The University of
Texas Medical Branch (UTMB), Galveston, TX, USA; Combined Degree Program,
UTMB, Galveston, TX, USA
Lawrence C. Sowers Department of Pharmacology and Toxicology, The U
­ niversity
of Texas Medical Branch (UTMB), Galveston, TX, USA; Department of Internal
Medicine, Division of Oncology, UTMB, Galveston, TX, USA
Ronan Swords Sylvester Comprehensive Cancer Center, University of Miami,
Miami, USA
Ana Luísa Teixeira Instituto Português de Oncologia do Porto Francisco G ­ entil,
EPE, Grupo de Oncologia Molecular—CI, Porto, Portugal; ICBAS, Abel Salazar In-
stitute for the Biomedical Sciences, University of Porto, Porto, Portugal; LPCC Re-
search Department-Portuguese League Against Cancer (NRNorte), Porto, ­Portugal
Mesut Tez Department of General Surgery, Ankara Numune Research and ­Training
Hospital, Ankara, Turkey
Claudio Tripodo Tumor Immunology Unit, Human Pathology Section, D
­ epartment
of Health Sciences, University of Palermo, Palermo, Italy
Naoto T. Ueno Department of Breast Medical Oncology, Morgan Welch
­Inflammatory Breast Cancer Research Program and Clinic, The University of Texas
MD Anderson Cancer Center, Houston, TX, USA
Angelo Vacca Department of Biomedical Sciences and Human Oncology (DIMO),
Section of Internal Medicine and Clinical Oncology, University of Bari Medical
School, Bari, Italy
Selahattin Vural Department of General Surgery, Ankara Numune Research and
Training Hospital, Ankara, Turkey
Chapter 1
The Role of Inflammation in Lung Cancer

Mónica Gomes, Ana Luísa Teixeira, Ana Coelho, António Araújo

and Rui Medeiros

Abstract Lung cancer remains a serious public health problem and is the first
cause of cancer death worldwide, and the overall 5-year survival rate for all stages
is 14–17 % for Non-small-cell lung cancer and 6 % for small-cell lung cancer.
Clinical and epidemiologic studies have suggested a strong association among
chronic infection, inflammation, and cancer. Immune system plays a critical role
in maintaining tissue homeostasis, cell turnover, tissue remodeling, and preventing

M. Gomes (*) · A. L. Teixeira · A. Coelho · R. Medeiros

Instituto Português de Oncologia do Porto Francisco Gentil, EPE, Grupo de Oncologia
Molecular—CI, Edifício Laboratórios, 4º piso Rua Dr. António Bernardino de Almeida,
Porto 4200-072, Portugal
e-mail: [email protected]
M. Gomes · A. L. Teixeira · R. Medeiros
ICBAS, Abel Salazar Institute for the Biomedical Sciences, University of Porto, Porto,
Portugal
A. Coelho
Faculty of Medicine of University of Porto, Porto, Portugal
M. Gomes · A. L. Teixeira · A. Coelho · R. Medeiros
LPCC Research Department-Portuguese League Against Cancer (NRNorte), Porto, Portugal
R. Medeiros
CEBIMED, Health Sciences Faculty, Fernando Pessoa, University of Porto, Porto, Portugal
A. Araújo
Chief of the Medical Oncology Service of Centro Hospitalar do Porto, Porto, Portugal
A. Araújo
Chief of the Medical Oncology Service of Centro Hospitalar de Entre Douro e Vouga, Santa
Maria da Feira, Portugal
A. Araújo
Instituto de Ciências Biomédicas de Abel Salazar, Porto, Portugal

B. B. Aggarwal et al. (eds.), Inflammation and Cancer, Advances in Experimental 1

Medicine and Biology 816, DOI: 10.1007/978-3-0348-0837-8_1, © Springer Basel 2014
2 M. Gomes et al.

infection and cell transformation. The inflammatory component in the development

of the neoplasm includes a diverse leukocyte population; these components are
considered inflammatory tumor key factors promoting tumor progression due to
its ability to release a variety of cytokines, chemokines, and cytotoxic mediators
such as reactive oxygen species (ROS), metalloproteinases, interleukins, and inter-
ferons. Cancer-related inflammation affects many aspects of malignancy, including
the proliferation and survival of malignant cells, angiogenesis, tumor metastasis,
and tumor response to chemotherapeutic drugs and hormones. Moreover, epide-
miologic studies and meta-analysis have shown that prolonged use of non-steroid
anti-inflammatory (NSAID) drugs reduces the risk of several solid tumor includ-
ing lung cancer. Strong lines of evidence suggest that the chemopreventive proper-
ties of chronic NSAID administration are based on their COX-inhibitory activity.
However, the prevention is a much better and more economical way to fight
against cancer than treating an already advanced and often incurable disease.

1.1 Introduction: Incidence, Survival, Major Gene

Products and Current Therapies for Lung Cancer

In 2008, about 12.7 million cancer cases and 7.6 million cancer deaths are
estimated to have occurred in this year in worldwide, with 56 % of cases and
64 % of the deaths in the economically developing world (Jemal et al. 2011).
Lung cancer was found to be the most commonly diagnosed cancer as well as
the primary cause of cancer-related mortality for males worldwide and the sec-
ond leading cause of cancer-related deaths for women (Jemal et al. 2011; Siegel
et al. 2012). For the year 2012, it is estimated that lung cancer will account for
26 % of all female cancer deaths and 29 % of all male cancer deaths (Siegel et al.
2012). Breast cancer in females and lung cancer in males are the most frequently
diagnosed cancers and the leading cause of cancer death for each sex in both eco-
nomically developed and developing countries, except lung cancer is preceded by
prostate cancer as the most frequent cancer among males in economically devel-
oped countries (Jemal et al. 2011).
Lung cancer was the most commonly diagnosed cancer as well as the leading
cause of cancer death in males in 2008, globally. Among females, it was the fourth
most commonly diagnosed cancer and the second leading cause of cancer death
(Jemal et al. 2011; Ferlay et al. 2010). Lung cancer accounts for 13 % (1.6 mil-
lion) of the total cases and 18 % (1.4 million) of the deaths in 2008 (Ferlay et al.
2010; Jemal et al. 2011).
The observed variations in lung cancer rates and trends across countries or
between males and females within each country largely reflect differences in the
stage and degree of the tobacco epidemic (Jemal et al. 2011).
Lung cancer can be divided into two major groups: small-cell lung cancer
(SCLC) and non-small-cell cancer (NSCLC) (Hoffman et al. 2000; Molina et al.
2008), NSCLC accounts for approximately 85 % of all cases of lung cancer
1 The Role of Inflammation in Lung Cancer 3

(Molina et al. 2008; Araujo et al. 2007). These lung cancer cells can again be
categorized based on their histological characteristics as squamous cell carci-
noma, large cell carcinoma, and adenocarcinoma (Tang et al. 2013). NSCLC
spreads slower than SCLC, so many patients who are diagnosed at an earlier stage
are potentially curable, though NSCLC may often relapse at other metastatic site.
Furthermore, NSCLC is generally less responsive to chemotherapy than SCLC,
so that even with surgical resection at early diagnosis, approximately 50 % of
NSCLC patients face recurring cancers (Tang et al. 2013).The 1-year survival rate
for lung cancer was 43 % in 2003–2006. However, despite extensive preclinical
and clinical research, the overall 5-year survival rate for all stages is still as low as
14–17 % for NSCLC (Araujo et al. 2007; Peebles et al. 2007) and even lower in
SCLC (6 %) (Wu et al. 2012).
In recent years, knowledge concerning the molecular mechanisms underly-
ing cellular transformation and development of cancer has been greatly expanded
(Araujo et al. 2007). Alteration of the major cell signaling and regulatory path-
ways either by overexpression or gene sequence variation is a frequent event in
lung cancer. These changes include alterations in receptor tyrosine kinases (TKs),
such as epidermal growth factor receptor (EGFR), and alterations in angiogenesis
pathways, apoptosis, proteasome regulation, and cell cycle control, among others
(Molina et al. 2008).
The EGFR is a tyrosine kinase that contributes to the regulation of cellular
homeostasis. It is a 170-KDa membrane protein that stimulates downstream cell
proliferation, survival, and tumorigenesis (Wheeler et al. 2010; Cohen 1965).
EGFR has been implicated in the growth of several human epithelial malignancies,
including lung cancer. It is overexpressed in several cancers, including approxi-
mately 40–80 % of NSCLC, which made EGFR a popular target for new drug
treatment exploration (Tang et al. 2013).
The ALK tyrosine kinase receptor has gained much attention recently as a
newly emerging relevant biomarker and therapeutic target in NSCLC (Wu et al.
2012). The activation of ALK is primarily through the formation of fusion genes.
EML4-ALK translocation is the most common ALK gene rearrangement. This
rearrangement in NSCLC patients is mainly found in younger non-smoking
patients with adenocarcinoma (Wu et al. 2012; Kwak et al. 2010). EML4-ALK
rearrangements are mutually exclusive with EGFR or KRAS mutations (Wu et al.
2012; Li et al. 2013). It has been reported that approximately 2–11 % of tumors
carrying positive EML4-ALK (Li et al. 2013).
KRAS mutations are a negative predictor of response to EGFR TKs, mainly
accounting for primary resistence (Linardou et al. 2008; de Mello et al. 2011).
Most KRAS mutations in lung adenocarcinoma are associated with smoking.
KRAS positive mutations are limited to NSCLC and are mutually exclusive to
mutations in EGFR and ALK (Linardou et al. 2008; Wu et al. 2012).
Lung cancer is a very aggressive cancer and its treatment still remains a chal-
lenge for health professionals. Conventional treatments are based on surgery, radi-
ation therapy, and chemotherapy. The selection of therapeutic regimen is based on
the cancer type (small-cell or non-small-cell), stage of disease, patient’s functional
4 M. Gomes et al.

ability, and genetic characterization (Wu et al. 2012; Tang et al. 2013; Hoffman
et al. 2000).
The majority of stage I through stage IIIA lung cancer patients generally choose
surgery as their primary option. Another popular option is preoperative chemo-
therapy, which has been shown to improve survival rate in patients with NSCLC.
Patients who require complete resection and no preoperative chemotherapy usually
invest in adjuvant chemotherapy. For patients with unresectable NSCLC, RT and
chemotherapy are excellent options for treatment (Tang et al. 2013). Further, cer-
tain agents have been combined with the chemotherapy to enhance its effects. The
anti-vascular endothelial growth factor agent, bevacizumab, for example, when
combined with chemotherapy, has resulted in increased survival rate when com-
pared to chemotherapy treatment alone (Tang et al. 2013).
For first-line chemotherapy, a platinum-based two-drug combination is sug-
gested for patients (Azzoli et al. 2009; Molina et al. 2008). Studies show that the
cisplatin, when used in combination chemotherapy, is associated with improved
response rates, no change in survival rate, and increased toxicity when compared
with the carboplatin (Tang et al. 2013). Also, another drug bevacizumab has dem-
onstrated great potential when used in combination with carboplatin or paclitaxel
in NSCLC patients (Tang et al. 2013; Molina et al. 2008).
The second-line chemotherapy treatment options, after primary treatment fails
to yield effective results, do differ from the first-line drugs. Approximately 30 %
of NSCLC patients who undergo first-line cancer treatment are candidates for
second- or third-line therapeutics. The first agent that was approved for second-
line therapeutics was docetaxel (Fossella et al. 2000). Other drugs that were also
soon approved include pemetrexed, erlotinib, and gefitinib (Tang et al. 2013).
Undergoing research is currently evaluating other possible strategies for second-
line therapeutics.

1.2 Inflammatory Signaling Pathways Associated with

Lung Cancer

Cancer is a hyperproliferative disorder that involves morphological cellular trans-

formation, dysregulation of apoptosis, uncontrolled cellular proliferation, invasion,
angiogenesis, and metastasis (Lin and Karin 2007; Hanahan and Weinberg 2011).
Clinical and epidemiologic studies have suggested strong association between
chronic infection, inflammation, and cancer (Coussens and Werb 2002; Lin and
Karin 2007; Ribeiro et al. 2007). Up to 20 % of cancers are linked to chronic
infections, 30 % can be attributed to tobacco smoking and inhaled pollutants
(such as silica and asbestos), and 35 % to dietary factors (20 % of cancer burden is
linked to obesity) (Aggarwal et al. 2009).
Approximately 150 ago, Virchow postulated that inflammation is a predisposing
factor of tumorigenesis (Lu et al. 2006; Balkwill and Mantovani 2001; Schottenfeld
and Beebe-Dimmer 2006). This hypothesis was based on his observation that
1 The Role of Inflammation in Lung Cancer 5

Fig. 1.1  Oncogenic evolution (adapted from Bremnes et al. 2011)

cancerous tissue often arose at sites of chronic inflammation and that inflammation
cells were present in the resect tumors (Bremnes et al. 2011; Mantovani et al. 2008;
Balkwill and Mantovani 2001). In contrast, Burnet proposed, in 1970, the concept
of immunological surveillance: the immune system spontaneously identifies and
eliminates cancer cells, thus protecting against tumor development (Bremnes et al.
2011; Van Ginderachter et al. 2006) (Fig. 1.1).
During the last decades, and according to Virchow hypothesis, epidemiological
studies have shown that individuals prone to chronic inflammatory diseases have
an increased risk of cancer development and that the underlying infections and
inflammatory responses have been linked to 15–20 % of all cancer deaths world-
wide (Bremnes et al. 2011).
The ultimate recognition of inflammation as a major player in cancer develop-
ment was reinforced with the 2011 update article on cancer hallmarks by Hanahan
and Weinberg, where it was classified as an enabling characteristic of tumors
(Mantovani et al. 2008; Hanahan and Weinberg 2011).
These evidence gathered over the last years showed that inflammation con-
tributes to the appearance of multiple cancer hallmark capabilities by supplying
important molecules to the tumor microenvironment. Those molecules include
growth factors that sustain the proliferative signaling, survival factors that limit
apoptosis, pro-angiogenic factors, extracellular matrix-modifying enzymes that
favor angiogenesis, invasion, and metastasis (Ben-Baruch 2006). Furthermore,
inflammation manifestations are observed at the earliest stages of tumor progres-
sion and are capable of nurturing insipient neoplasias into developed cancers.
In addition, inflammatory cells can release a number of chemicals, such as ROS,
6 M. Gomes et al.

that are actively mutagenic and promote malignancy even further (Hanahan and
Weinberg 2011).
Immune system plays critical roles in maintaining tissue homeostasis, cell
turnover, tissue remodeling, and preventing infection and cell transformation. It
is composed of two distinct compartments mediating innate and adaptive immune
response. Each compartment has, through a diversity of cells and soluble mediators,
advanced communication networks, which enable rapid and effective responses to
tissue injury (Bremnes et al. 2011).
Although it is clear that inflammation itself is not the cause of the onset of can-
cer cell proliferation, a sustained atmosphere rich in inflammatory cells, growth
factors, and promoters activated stromal DNA damage may enhance and/or pro-
mote risk for the emergence of malignancies. This tumor microenvironment is
composed not only by resident tissue cells such as fibroblasts and endothelial cells
but also by infiltrating host leukocytes (Ben-Baruch 2006). Tumor cells produce
several cytokines and chemokines that attract leukocytes. Several inflammatory
cytokines have been implicated to mediate different steps in the pathway leading
to carcinogenesis. Increased serum levels of pro-inflammatory interleukins IL-1β,
IL-6, IL-8, IL-12, and IL-18 have been observed in different types of cancer,
including lung cancer (Tsai et al. 1999; Srivani and Nagarajan 2003; Michalaki et
al. 2004; Ye et al. 2007; Azevedo et al. 2011).
On the other hand, the pleiotropic anti-inflammatory interleukins, IL-4 and
IL-10, stimulate the growth of many tumors, such as ovarian, prostate, and lung
although they have an inhibitory effect on growth or invasion of other types of
cancer (Toi et al. 1992; Takeshi et al. 2005; Lan et al. 2006; Gomes et al. 2012)
(Fig. 1.2).
The inflammatory component in the development of the neoplasm includes a
diverse leukocyte population, which stand macrophages (abundant in many types
of tumors), lymphocytes, natural killer (NK) cells, neutrophils, and dendritic cells.
These components are considered inflammatory tumor key factors in pro-
moting tumor progression due to its ability to release a variety of cytokines,
chemokines, cytotoxic mediators such as reactive oxygen species, metallopro-
teinases (MMPs) and agents perforator membrane, and soluble mediators of cell
death, such as TNF-α (Tumor Necrosis Factor-α), interleukins (IL), and interfer-
ons (IFNs) (Coussens and Werb 2002).
Many of the mediators released during chronic inflammation promote unregu-
lated cell proliferation and invasion, induce angiogenesis, and increase mutagen-
esis. Due to these characteristics, the transformation and initiation of a malignant
phenotype may occur and tumor progression may be promoted. In addition, many
of the factors released by inflammatory cells may lead directly or indirectly to a
marked suppression of the immune response, which otherwise could have an
important role in tumor eradication (Ben-Baruch 2006).
The lung cancer tumor microenvironment is composed of extracellular matrix,
tumor cells, fibroblasts, inflammatory cells, vascular and lymphatic endothelial
cells, growth factors, cytokine, chemokines, hormones, proteases, among oth-
ers. Fibroblasts exist normally in the connective tissue and produce extracellular
1 The Role of Inflammation in Lung Cancer 7

Fig. 1.2  The tumor microenvironment associated with inflammation and its consequence in can-
cer processes (adapted from Serefoglou et al. 2008)

matrix and collagen. They are essential in wound repairing but when exposed to
cigarette smoke, they secrete pro-inflammatory mediators such as prostaglandin-E2
(PGE2), IL-8, IL-6, and MCP-1, leading to a prolonged inflammatory response
(Martey et al. 2004). Macrophages are recruited by granulocyte colony-­stimulating
factor (G-CSF), GM-CSF, macrophage-stimulating protein (MSP), vascular
endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and
macrophage migration inhibitory factor (MIF).
It is known that macrophages can be activated in response to microbiological
agents and in particular cytokines interferon-γ (IFN-γ) (classical macrophage acti-
vation). However, it was recently discovered that anti-inflammatory molecules,
such as glucocorticoid hormones and cytokines IL-4, IL-13, and IL-10, induce a
different program activation of macrophages (alternative macrophage activation)
(Sica et al. 2006; Mantovani et al. 2002, 2004). Tumor-associated macrophages
(TAM) that interact with tumor cells to produce cytokines and growth factors
that influence tumor development have two different phenotypes: M1 and M2
(O’Callaghan et al. 2010). The M1 macrophages have been associated with better
prognosis in NSCLC, are efficient immune cells and are associated with an anti-
tumor behavior (Bremnes et al. 2011). Nonetheless, the most prevalent phenotype
is the M2, which promotes tumor growth, angiogenesis, invasion, and metastasis.