Yonago Acta medica 2014;57:65–72

Review Article: Special Contribution

Inflammation-Related Carcinogenesis: Current Findings in Epidemiological Trends,
Causes and Mechanisms
Futoshi Okada*†*Division of Pathological Biochemistry, Department of Biomedical Sciences, School of Life Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan and †Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan

ABSTRACTInflammation is a definite cancer-causing factor as revealed by cumulative basic, clinical and epidemiological studies. It is mostly induced by infectious agents.
For instance, infection with papillomaviruses associateswith anogenital cancers, especially cervical cancers;
Helicobacter pylori infection of the stomach tends toincrease the risk of stomach cancer; chronic hepatitis
B & C viruses and fluke infections of the liver increase
liver cancers; autoimmune diseases, e.g., inflammatory
bowel diseases, associate with development of colorectal cancer, and aerial irritants (foreign bodies) such as
asbestos or fine particulate matter (PM2.5) in outdoor
air increase malignant pleural mesotheliomas or lungcancers. These are typical examples of inflammationrelated carcinogenesis. It is apparent that the pathogens
to induce inflammatory reactions in specific organs
are not related to each other. However, the underlying
pathogenesis in common is to induce and/or sustain
inflammation. In this article, I would like to review the
up-to-date findings of epidemiological trends, causes
and mechanisms of inflammation-related carcinogenesis.
Key words

low-grade chronic inflammation, which is characterized
by increased systemic levels of inflammatory cytokines
and inflammation-responsible protein (C-reactive
protein), is one of the underlying key mechanisms.1
Indeed, estimated 20–25% of all cases of cancer
worldwide are associated with inflammation induced by
microbial infection. Extended life span, dietary factors
and physical inactivity; mutation and replicating errors;
environmental pollutants including aerial irritants andtobacco; and radiation and ultraviolet are linked to carcinogenesis today. Nevertheless, persistent inflammation resulting from infection or autoimmunity is mostevidently associated with the onset of carcinogenesis.2
The relation of inflammation to cancer was first
postulated by Galenus around 1,800 years ago.3 He proposed that tumors arose from inflammatory tissue injury
and that the tumors and the tissue were pathophysiologically similar.3 Centuries later in 1863, Virchow
confirmed Galenus’s hypothesis from his own observation that lymphoreticular infiltrates, namely inflammation, preceded tumor development.4 This possible link
between injurious inflammation and cancer was also
pointed out later by Dvorak who revealed that tumor tissues resembled wound tissues because both tissues werecomposed of similar stromal cell types such as infiltrated inflammatory cells and angiogenesis-related cells; theonly difference he pointed out was that tumor tissues did
not terminate (heal) but wound healed finally.5
Undoubtedly antitumor immunity exists, since particular kinds of tumors are formed only in patients with
iatrogenic immunosuppression such as melanoma andnonmelanoma skin cancer in organ transplant recipients, lymphoma in patients with lymphoproliferative
disorders, or Kaposi’s sarcoma in patients with immunosuppressive infection such as with HIV. However,
the generality of the arising tumors are sarcomas andhematologic malignancies, and carcinomas that accountfor the majority of human carcinogenesis seldom occur
in the immunosuppressed patients. Discussions havesuggested that antitumor immunity might work only inthe very initial phase of carcinogenesis or work against
particular kinds of tumorigenesis only. An opinion haseven suggested that antitumor immune effector cells
may act as stimulant to carcinogenesis. In the 1970s,

carcinogenesis; inflammation; mousemodel
Cancer is classified as noncommunicable disease as
cardiovascular diseases, chronic respiratory diseases
and diabetes are. They are mostly chronic diseases oflong duration and generally slow development. Whilethey are assumed to develop from aging, urbanization,and unhealthy lifestyles, it has also become known that
Corresponding author: Futoshi Okada, PhD
fuokada@med.tottori-u.ac.jp
Received 2014 May 29
Accepted 2014 May 29
Abbreviations: COPD, chronic obstructive pulmonary disease;
EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis
C virus; HDV, hepatitis D virus; HERV-K, human endogenous
retrovirus type K; HIV-1, human immunodeficiency virus; HPV,
human papillomavirus; HTLV-1, human T-cell lymphotropic
virus type 1; JCV, JC virus; KSHV, Kaposi sarcoma herpes virus;
MCV, molluscum contagiosum virus; Mn-SOD, manganeseSOD; PM, particulate matter; QR cells, regressive cells; ROS,
reactive oxygen species; SOD, superoxide dismutase.

65

F. OkadaPrehn proposed that immune effector cells contributed
to carcinogenesis, and named the phenomenon as “immunostimulation theory of tumor development.”6
From the achievements of our predecessors carriedout over the two millennia, we have solid evidence thatan inflammatory environment can be an essential risk
for induction of various types of carcinomas. Recent
results add that inflammation-related carcinogenesis is
influenced not only by individual age and sex, but also
by regional/geographical and economical development
statuses of country. I review the current evidence on the
inflammation-related carcinogenesis and propose possibly effective preventive/therapeutic strategies based on
our elucidation of inflammation mechanism obtained byusing our animal model.

of each country; i.e., the standard of life, the levels of
medical care and education, etc. will make up the characteristic of a country as a whole. In addition, prevalenceof the four main infectious agents, HPV, HBV, HCV andHelicobacter pylori, differs among economically andgeographically different regions. Relative contribution of
HPV to cancer burden is similar in both developed anddeveloping countries. However, that of Helicobacter pylori is larger in developed countries, and those of HBVand HCV are larger in developing countries.10
There were estimated 14.1 million new cancer casesand 8.2 million cancer deaths globally in 2012; of thecancer deaths, about 65% (5.3 million) was in less developed countries.11 Since the infectious agents accountfor as much as 20% of all of the cancer-causing factors,
we could estimate that around 2.8 million new cancer
cases and around 1.7 million deaths would be attributable to infection/inflammation. It is greatly apprehended
that new cancer cases/deaths due to inflammation would
increase rapidly in the developing countries within a few
decades as a result of upcoming population growth.12
Although the total number of cancer cases due to
inflammation is much the same between men and women,10 there are some sex- and age-dependent differencesin particular cancers: stomach cancer, liver cancer, oropharynx cancer, bladder cancer, Hodgkin’s lymphoma
and Kaposi’s sarcoma are much higher in men than inwomen.10 And it is obvious that around 30% of inflammation-related cancers (cervical cancer, Hodgkin’s lymphoma and Kaposi’s sarcoma) are in individuals younger
than 50 years, compared to other inflammation-related
cancers which develop mostly in those older that 50
years.10

EPIDEMIOLOGICAL TREND OF INFLAMMATIONRELATED CARCINOGENESISIt is obvious that incidences of inflammation-related
cancers are not in a homogenous background but in acomplex one influenced by individual age, sex, living
region, era and also development status of country as
revealed in the recent epidemiological studies.
Chronologically the incidences of inflammationrelated carcinogenesis also differ. In the United States,
cancer epidemiologists estimated in the 1980’s thataround 75% of cancers was due to three cancer-causing
factors: daily diet, smoking and infection/inflammation.7
Currently the three major factors are thought to accountfor 43% of cancer causes.8 Involvement of inflammationin the total cancer incidences was reduced from 10% to
5%.9There are geographical differences in the incidencesof inflammation-caused cancers. Namely, contributionof inflammation to carcinogenesis greatly varies amongcontinentals, countries, and even in the regions within acountry. Figure 1 shows the ratios of infection/inflammation to all the cancer death causes: around 25% in
sub-Saharan Africa, around 6% in Europe.8 In general,the proportions were higher in less developed countries(23%) than in more developed countries (7%) including
North America and Europe (10). Lowest ratios were inAustralia and New Zealand (3%), while other parts of
Oceania showed higher ratios (18%). In contrast to thehighest ratio in sub-Saharan Africa (25%), the rates arelower in North Africa and west Asia (13%). In east Asia,
the rates are high: Japan (20%), China (26%), South Korea (21%) and India (21%).10 Considering the high ratios,
east Asia including Japan is still a developing region.
The geographical and regional differences in theincidences of inflammation-related carcinogenesis may
arise from the economic standing or development status

CAUSES OF INFLAMMATION-RELATED CARCINOGENESISInfections induced by certain viruses, bacteria, parasites
or foreign bodies and following prolonged inflammation
have been identified as grave risk factors for development of specific cancers. Table 1 shows infectious agentsclassified as definitely carcinogenic to humans by theInternational Agency for Research on Cancer and thoseclassified as presumably carcinogenic according to experimental and clinical reports.10
MECHANISMS OF INFLAMMATION-RELATEDCARCINOGENESIS DETERMINED IN AN EXPERIMENTAL MODEL
Close association between inflammation and carcinogenesis has been indicated by clinical and epidemiological studies; however, there is hardly a solid animalmodel in which carcinogenesis by inflammation can
66

Inflammation-related carcinogenesis

Fig. 1. Causes of cancer differ from country to country. Europe, excluding east Europe; Africa, representing sub-Saharan countries only.

be evidently observed. To demonstrate the direct link
between inflammation and carcinogenesis, our group
established several animal models in which tumorigenic
conversion or acceleration of carcinogenic processesof rat, mouse or human cells occurs in the presence of
inflammation. In this section, I summarize the resultsof our thorough investigation using one of our mousemodels and introduce our elucidation of the mechanism
responsible for inflammation-related carcinogenesis andtheoretical preventive strategies.
To establish the experimental model for carcino
genesis especially focusing on acquisition of tumori
genicity in vivo, we had to choose cells which wereimmortalized, non-tumorigenic, and non-metastatic
but would grow in vitro, bearing the concept of
xenogenization in mind. “Xenogenization of tumor
cells” is the term meaning immunologically spontaneous
regression of tumor cells which have been infectedwith xenogeneic viruses,13 transfected with the genes
coding allogeneic antigen,14 or exposed to mutagenic
chemicals,15 after injected into normal syngeneic host.
We obtained regressive clonal QR cells from clonal
tumorigenic fibrosarcoma cells, BMT-11 cl-9, by exposing them in vitro to a mutagen/carcinogen (quercetin);they were non-tumorigenic and non-metastatic in normal syngeneic C57BL/6 mice, and we termed the phenomenon as “chemical xenogenization of tumor cells.”15
By using the regressive QR cells, we can easily detect
internal/external factors which are closely associatedwith carcinogenic process through the conversion of
their regressive phenotypes into lethally tumorigenic
ones, after injecting QR cells previously treated in vitro
with a candidate material, or co-implanting QR cellswith it, into mice. As shown in the Fig. 2A, QR cells did
not develop tumor after (2 × 105 cells) subcutaneously
injected into mice.15 Since QR cells grew progressively
in immunosuppressed hosts, we determined that theirregression was mediated by host immunity.16
Infiltrated inflammatory cells are necessary andsufficient to accelerate carcinogenesis

A serendipitous finding was that the regressive QR cells
were spontaneously converted to grow lethal after implanted into a pre-inserted piece of hemostasis gelatin
sponge which induced foreign-body-reactive inflammation at the implantation site (Fig. 2B).17 Significanceof the foreign-body-induced inflammation on carcinogenesis was confirmed by using other materials such as
plastic plate. In this case, too, various phenotypic alterations occurred following QR cell conversion.18 All of thearising tumors were found to have acquired tumorigenic
and metastatic phenotypes, and the acquired malignant
phenotypes remained stable as far as examined for decades at least under cultivation in vitro. An increase inprostaglandin E2 production followed the acquisitionof tumor-forming ability, which particularly suppressed
immunological host-defense against tumors. Angiogenesis, motility and invasion capacities of tumorigenic
67

F. Okada
Table 1. Definitely and presumably carcinogenic agents in inflammation-related carcinogenesis in humanSites of inflammationrelated carcinogenesis

Causes of inflammation/pathological condition
Definitely carcinogenic
Presumably carcinogenic

Eye
HIV type 1
Lip		
Oral cavity
HPV type 16
Salivary gland		
Tongue		Tonsils
HPV type 16
Nasopharynx
EBV
Pharynx
HPV type 16
Oropharynx		
LarynxAsbestos
Thyroid		Esophagus		
		
Lung
Asbestos, coal gasification, outdoor
air pollution,* tobacco smoke
Lung mesothelium
Asbestos
Breast		StomachHelicobacter pylori
Liver
HBV, HCV, Clonorchis sinensis,
Opisthorchis viverrini
Bile duct
Clonorchis sinensis,
Opisthorchis viverrini
Gall bladder		Pancreas				Colon & Rectum		
		
		
		
		
Bladder
Schistosoma haematobiumAnus
HIV type 1, HPV type 16
Prostate				
Ovary
Asbestos
Uterine cervix
HPV types 16, 18, 31, 33, 35, 39,
45, 51, 52, 56, 58, 59; HIV type 1
Endometrium		Penis
HPV type 16
Vulva
HPV type 16
VaginaHPV type 16
Skin
UV-associated skin inflammation
Melanoma		Non-melanomatous
skin cancer		Central nerve		
Endothelium
HIV type 1, KSHV
(Kaposi’s sarcoma)
Vasculature		
Hodgkin’s lymphoma		
Lymphoma
EBV, HCV, HIV type 1,
HTLV-1, KSHV
Orbital lymphoma		
Thyroid lymphoma		
Lymphoma in the
Pyothorax-associated lymphoma
pleural cavity
MALT lymphoma
Helicobacter pylori
Small-bowel lymphoma		UV-associated skin inflammation
UV-associated skin inflammation
HPV type 18, gingivitis, lichen planus, leukoplakia
Sialadentis
HPV, caries, gingivitis
Asbestos
HPV
HPV type 16
Chronic lymphocytic thyroiditis, Hashimoto’s thyroiditis
Gastric reflux, esophagitis, Burrett’s esophagus,
Neisseria mucosa, Neisseria sicca, Neisseria subflava
Asthma, bronchitis, COPD, interstitial pneumonia, sarcoidosis,
silicosis, tuberculosis, Chlamydia pneumoniae
Silicosis
HERV-K, inflammatory breast cancer
Asbestos, EBV, chronic atrophic gastritis
HDV, HIV type 1, Schistosoma japonicum, hemochromatosis
alpha-1-anti-trypsin deficiency, alcohol
Bile acids-associated cholangitis
Gall bladder stone-associated cholecystitis, Salmonella typhimurium
Chronic pancreatitis, alcoholism-associated pancreatitis,
hereditary pancreatitis, primary sclerosing cholangitis, alcohol
Bile acids-associated coloproctitis, inflammatory bowel diseases,
cytomegalovirus, EBV, HPV, JCV, Bacteroides,
Clostridiumsepticum, Escherichia coli, Helicobacter pylori,
Streptococcus bovis, Streptococcus gallolyticus,
Schistosoma japonicum, asbestos
Cystitis, urinary catheter-associated cystitis
HPV types 18, 33, anal fistula
Prostatitis, proliferative inflammatory atrophy, gonorrhea, chlamydia,
mumps virus, Trichomonas vaginalis
Pelvic inflammatory disease
HPV types 26, 53, 66, 67, 68, 70, 73, 82;
herpes simplex virus
Endometriosis
HIV type 1, HPV type 18
HIV type 1, HPV types 18, 33; lichen sclerosis
HIV type 1
Chronic osteomyelitis, HIV type 1, HPV types 5, 8; MCV
UV-associated skin inflammation
Cutaneous HPV types
JCV
HIV-2
Bortonella
EBV, HIV type 1
HIV type 2, Hashimoto’s thyroiditis, Sjögren’s syndrome,childhood celiac disease, HBV, HTLV-1
Chlamydia psittaci
Hashimoto’s thyroiditis

Campylobacter jejuni
Continued on the following page68

Inflammation-related carcinogenesis
Table 1–Continued
Sites of inflammationrelated carcinogenesis

Causes of inflammation/pathological condition
Definitely carcinogenic
Presumably carcinogenic

Cutaneous lymphoma		
DLBC lymphoma		
Adult T-cell leukemia
ATL (HTLV-1)
T-cell lymphoma		
Burkitt’s lymphoma
EBV
B-cell lymphoma 		Primary effusion lymphoma

Borrelia burgdorfer
Helicobacter pylori
EBV
EBV
KSHV

ATL, adult T-cell leukemia; COPD, chronic obstructive pulmonary disease; DLBC, diffuse large B-cell lymphoma; EBV, Epstein-Barrvirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HERV-K, human endogenous retrovirus type K; HIV-1,
human immunodeficiency virus; HPV, human papillomavirus; HTLV-1, human T-cell lymphotropic virus type 1; JCV, JC virus; KSHV,
Kaposi sarcoma herpes virus; MALT, mucosa-associated lymphoid tissue; MCV, molluscum contagiosum virus.
*Outdoor air pollutions with PM10, PM2.5, NO2, SO2 and O3•PM2.5.

cells converted from QR cells were also augmented inparallel with their malignant potential.18 Histologically,
we observed emergence of abundant microvilli on thesurface of the tumorigenic cells, a common phenomenon
observed in other malignant tumor cell lines of rodent
and human.19
We also determined several gene alterations throughthe inflammation-mediated conversion in this model(Fig. 3). The level of thymosin beta4 gene, which is
known to be an actin-regulating protein and function forangiogenesis and wound healing, was elevated in all of
the arising tumor cells. From the results of sense and antisense cDNA transfection experiments, we revealed thatthymosin beta4 gene was responsible for tumor forming and/or metastasis through regulating cell motility.20
The expression of E1AF, a member of the ets oncogenictranscription factor, was found high in the arising tumorlines.21 E1AF regulates tumor cell motility and invasive
activities through induction of membrane-type 1-matrix
metalloproteinase (MT-1-MMP) which converts the latent form of matrix metalloproteinase-2 (MMP-2) into
active form.21 Thus E1AF makes tumor cells invasive.21
We used foreign bodies to induce inflammation at
the implanted site locally, which was to demonstrate
direct association between inflammation and carcinogenesis in vivo. Evidence for the effects of inflammatory
cells on carcinogenesis was also demonstrated by thefollowing three experiments: i) By histological examination, we found that neutrophils predominantly infiltrated
into the inserted gelatin sponge in the very early phase.22
One of the features of using gelatin sponge is that it ispossible to collect the infiltrated inflammatory cells bytreating the sponge with collagenase (Fig. 4). It was clearthat inflammation definitely contributed to the conversion of QR cells, since we found that the inflamed cells
separated from the sponge could alter QR cells into le-thally tumorigenic ones in the experiment of mixing theboth two kinds of cells and injecting them in mice (Fig.
2C).22 ii) To confirm the role of infiltrated neutrophils ininflammation, we eliminated neutrophils by administering anti-neutrophil antibody (RB6). As a result, nearly
all the arising tumors in the mice, non-treated or treatedwith control IgG, acquired malignant phenotypes. On
the other hand, in RB6 antibody-administered mice,arising tumors did not acquire malignant phenotypes

Fig. 2. A mouse model of inflammation-related carcinogenesis.
Regressive cells (QR) spontaneously regress in syngeneic normal
mice after subcutaneous injection (A). Tumorigenic conversion
was observed in QR cells injected into subcutaneously preinserted gelatin sponge (B). Tumorigenic conversion was also
observed in QR cells which were mixed with gelatin-spongeinfiltrated inflammatory cells and injected in mice (C). The
model was also utilized to screen candidate drugs to prevent
inflammation-related carcinogenesis (D).

69

F. OkadaFig. 3. Alteration of key molecules through foreign-body-induced carcinogenesis in mice. A diagram of stepwise molecular alterations in
QR cells associated with acquisition of malignant phenotypes, accelerated by inflammation.

(Fig. 2D).22 iii) We further confirmed the results in
integrin-beta-2 knockout mice (C57BL/6JItgb2tm1Bay
equivalent to CD18-deficient). Integrin-beta-2 is the key
adhesion molecule for the migration of neutrophils into
an inflammatory region. Neutrophil infiltration into
gelatin sponge was abolished and acquisition of tumorigenic phenotypes was suppressed in the integrin-beta-2
knockout mice.22
These findings show that neutrophils are one of themain components of inflammation-associated tumor development and progression. Interestingly, the capabilityof neutrophils to accelerate tumor cell malignancy varies
depending on their activation phase, which we suggest
from the finding that circulating or bone marrow neutrophils do not convert regressive cells into malignant ones
but infiltrated (activated) neutrophils do.22

ROS produced by infiltrated inflammatory cells are
the major cause for carcinogenesis

We assumed that reactive oxygen species (ROS) would
be key molecules that stimulate carcinogenic processsince ROS act on both initiation and promotion of cancer. To determine the direct contribution of ROS to the
carcinogenesis in our model, we used gp91phox geneknockout mice. Bactericidal function of neutrophilsbrings about generation of superoxide anions by forming
NADPH oxidase complex (gp22phox, gp40phox, gp47phox,
gp67phox, gp91phox and Rac1/Rac2) from interaction withcytochrome b558. The frequency of tumor developmentfrom the QR cells co-implanted with gelatin sponge wasdecreased in the gp91phox–/– mice.23 To determine whether phagocyte-derived ROS were actually involved intumor development, we isolated phagocytes from wildtype mice and transferred them into gp91phox–/– mice.

Fig. 4. Advantages of using gelatin sponge for investigating inflammation-related carcinogenesi. There are advantages in using gelatin
sponge for analyzing the inflammation-related carcinogenesis since sponge-infiltrated inflammatory cells can be collected by briefcollagenase treatment. Then we can quantify inflammation by counting the number of infiltrated cells. Moreover, by using the infiltrated
cells, we are able to analyze the inflammation by biological, molecular genetical, and cytological methods.

70Inflammation-related carcinogenesis

As a result, wild-type-derived phagocytes increased
the frequencies of tumor development. In contrast, thephagocytes obtained from gp91phox gene-knockout mice
did not have such activity.23 Moreover, administrationof aminoguanidine, a broad inhibitor for inducible nitricoxide synthase, partially but significantly suppressed
conversion in the model;24 thus we concluded that nitricoxide (NO) was also involved in the process. These results show that ROS and NO, derived from foreign-bodyinduced inflammatory cells, are an intrinsic factor in theconversion of regressive cells to more malignant ones.

in turn, cause compensatory cell proliferation, which
will help accumulation of DNA damages/gene mutations and effectively incorporate internal/external carcinogenic factors into the growth of stimulated normal
cells. Apart from those, it has recently been revealed
that inflammatory environments accelerate epigenetic
alterations and the alterations could cause inflammationrelated carcinogenesis.26 All these events accompanying
inflammation are essential to carcinogenesis. In thissense, we may understand that an inflammatory environment is a niche for carcinogenesis.
Intriguingly, we noticed that all the chronic inflammation and dysregulated immunity do not always lead tocarcinogenesis; for instance, some of the chronic inflammatory diseases are not linked to cancer risk, and someare even leading to tumor regression. For instance, rheumatoid arthritis is not linked to cancer risk even though
the inflammatory regions in rheumatoid arthritis patientsshow mutations of tumor suppressor genes at similarfrequencies to those in the digestive tract tumors arising from chronic inflammatory reaction. Another thing
to be noted here is that parasite (helminth, Trichurissuis) could diminish inflammatory response, and now
its effects on inflammatory bowel diseases are underinvestigation. We may be able to determine the nature of
inflammation which accelerates carcinogenesis by comparing the typical two types of inflammation, i.e., procarcinogenic and anti-/unrelated-carcinogenic ones.
In our mouse model, inflammation induced by gelatin sponge insertion causes acute-phase inflammation,
which will not become chronic since the sponge is absorbed spontaneously in the body. The actual inflammation leading to carcinogenesis is mostly chronic; possibly
there is some link between acute-phase inflammationand chronic inflammatory diseases. A few techniques areavailable to pursue researches of this aspect: Apheresis
technology has made it possible to eliminate granulocytes and monocytes specifically from the patients withulcerative colitis. By meta-analysis study, those patientswith intensive granulocytes and monocytes adsorption
make the higher rate of shift to clinical remission.27 It
is important to find out whether there are some types ofregulatory inflammatory cells in the early phase of inflammation that may maintain and prolong inflammation.
We have not fully elucidated the mechanisms of inflammation: how chronic inflammation is induced, activated,maintained and resolved; whether chronic inflammationis triggered by preexisting acute inflammation or it develops independently. We should now move on to identify
key regulators for induction/maintenance of chronic inflammatory reaction that closely link to carcinogenesis,
among which acute-phase inflammatory cells may be.

Attempts to prevent inflammation-related carcinogenesis

When we determined the cause of inflammation-related
carcinogenesis, it appeared that the carcinogenesis
would be theoretically preventable: ROS are one of
the most crucial genotoxic mediators to accelerate the
carcinogenic process; then their antagonists, namely antioxidative enzymes or antioxidants, will be effective toprevent the process (Fig. 2D).
Accordingly, we tried to induce an antioxidative
enzyme, superoxide dismutase (SOD), at the inflammatory site, hopefully by administration of orally active
SOD, in our model. We used a newly developed SOD,
named oxykine; as a result, the incidence of tumor formation was significantly decreased due to induction ofmanganese-SOD (Mn-SOD) in the inflamed region,
compared to the one under control vehicle treatment.25 It
should be noted that Mn-SOD was induced secondarily
to activation of host intestinal immunity instead of the
drug’s direct action to the inflamed site. Thus Mn-SOD
was induced at the inflamed site and the inflammationrelated carcinogenesis was suppressed. Based on these,rationales for effective prevention of inflammationrelated carcinogenesis will be either by suppressing ROS
production of inflammatory cells or by blocking infiltration of inflammatory cells into the inflamed site.

CONCLUSION & PERSPECTIVE

Inflammation, especially chronic one, is the definite
cause for tumor development and progression, and it iswell referred to as “inflammation-related carcinogenesis”. The pathogens that cause various types of inflammation-related carcinogenesis are obviously unrelated,
whereas the essential pathological feature in common
is continuous inflammation: initially infiltration of activated phagocytes/lymphocytes and then stimulated
reaction of stroma composed mainly of fibroblasts andangiogenesis-related cells. It is assumed that continuous
generation of ROS and NO by these infiltrated inflammatory cells is likely to injure normal cells. This could,
71

F. OkadaAcknowledgments: I thank Ms Masako Yanome for her help in
English revision of this manuscript.

mor cells treated with quercetin or 5-azacytidine. Int J Cancer.
1987;39:338-42. PMID: 2434441.
16 Okada F, Hosokawa M, Hasegawa J, Ishikawa M, Chiba I,
Nakamura Y, et al. Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: diminutionof tumorigenicity with a corresponding decrease in the production of prostaglandin E2. Cancer Immunol Immunother.
1990;31:358-64. PMID: 2386981.
17 Okada F, Hosokawa M, Hamada JI, Hasegawa J, Kato M,
Mizutani M, et al. Malignant progression of a mouse fibrosarcoma by host cells reactive to a foreign body (gelatin sponge).
Br J Cancer. 1992;66:635-9. PMID: 1419599.
18 Okada F. Inflammation and free radicals in tumor development and progression. Redox Rep. 2002;7:357-68. PMID:
12625943.
19 Ren J, Hamada J, Okada F, Takeichi N, Morikawa K,
Hosokawa M, et al. Correlation between the presence of microvilli and the growth or metastatic potential of tumor cells.
Jpn J Cancer Res. 1990;81:920-6. PMID: 1977729.
20 Kobayashi T, Okada F, Fujii N, Tomita N, Ito S, Tazawa H, etal. Thymosin-beta4 regulates motility and metastasis of malignant mouse fibrosarcoma cells. Am J Pathol. 2002;160:86982. PMID: 11891186.
21 Habelhah H, Okada F, Kobayashi M, Nakai K, Choi S,
Hamada J, et al. Increased E1AF expression in mouse fibrosarcoma promotes metastasis through induction of MT1-MMP
expression. Oncogene. 1999;18:1771-6. PMID: 10208438.
22 Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y,
et al. Infiltration of neutrophils is required for acquisition ofmetastatic phenotype of benign murine fibrosarcoma cells:
implication of inflammation-associated carcinogenesis andtumor progression. Am J Pathol. 2003;163:2221-32. PMID:
14633597.
23 Okada F, Kobayashi M, Tanaka H, Kobayashi T, Tazawa H,
Iuchi Y, et al. The role of nicotinamide adenine dinucleotide
phosphate oxidase-derived reactive oxygen species in theacquisition of metastatic ability of tumor cells. Am J Pathol.
2006;169:294-302. PMID: 16816381.
24 Okada F, Tazawa H, Kobayashi T, Kobayashi M, Hosokawa
M. Involvement of reactive nitrogen oxides for acquisition ofmetastatic properties of benign tumors in a model of inflammation-based tumor progression. Nitric Oxide. 2006;14:122-9.
PMID: 16125421.
25 Okada F, Shionoya H, Kobayashi M, Kobayashi T, Tazawa H,
Onuma K, et al. Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma
cells by administration of an orally available superoxide dismutase. Br J Cancer. 2006;94:854-62. PMID: 16508635.
26 Niwa T, Toyoda T, Tsukamoto T, Mori A, Tatematsu M,
Ushijima T. Prevention of Helicobacter pylori-induced gastriccancers in gerbils by a DNA demethylating agent. Cancer
Prev Res. 2013;6:263-70. PMID: 23559452.
27 Yoshino T, Nakase H, Minami N, Yamada S, Matsuura
M, Yazumi S, et al. Efficacy and safety of granulocyte andmonocyte adsorption apheresis for ulcerative colitis: a metaanalysis. Dig Liver Dis. 2014;46:219-26. PMID: 24268950.

The author declares no conflict of interest.
References
1 Mathur N, Pedersen BK. Exercise as a mean to control
low-grade systemic inflammation. Mediators Inflamm.
2008;2008:109502. PMID: 19148295.
2 Loomis D, Grosse Y, Lauby-Secretan B, El Ghissassi F,
Bouvard V, Benbrahim-Tallaa L, et al. The carcinogenicity of outdoor air pollution. Lancet Oncol. 2013;14:1262-3.
doi:10.1016/S1470-2045(13)70487-X.
3 Trinchieri G. Cancer and inflammation: an old intuition
with rapidly evolving new concepts. Annu Rev Immunol.
2012;30:677-706. PMID: 22224761.
4 Balkwill F, Mantovani A. Inflammation and cancer: back to
Virchow? Lancet. 2001;357:539-45. PMID: 11229684.
5 Dvorak HF. Tumors: wounds that do not heal. Similarities
between tumor stroma generation and wound healing. N Engl
J Med. 1986;315:1650-9. PMID: 3537791.
6 Prehn RT, Lappé MA. An immunostimulation theory oftumor development. Transplant Rev. 1971;7:26-54. PMID:
4947774.
7 Doll R, Peto R. The causes of cancer: quantitative estimatesof avoidable risks of cancer in the United States today. J NatlCancer Inst. 1981;66:1191-308. PMID: 7017215.
8 Global action against cancer. Updated version [Internet].
Geneva: World Health Organization and International Union
Against Cancer; c2005 [cited 2014 May 28]. p. 12. Available
from: http://www.who.int/cancer/media/en/GlobalActionCancerEnglfull.pdf.
9 Kobayashi H. “One step” for cancer prevention. Asian Pac J
Cancer Prev. 2006;7:672-8. PMID: 17250451.
10 de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman
D, et al. Global burden of cancers attributable to infectionsin 2008: a review and synthetic analysis. Lancet Oncol.
2012;13:607-15. PMID: 22575588.
11 GLOBOCAN 2012: Estimated Cancer Incidence, Mortality
and Prevalence Worldwide in 2012 [Internet]. Lyon: International Agency for Research on Cancer; c2014 [cited 2014 May
28]. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.
12 Thun MJ, DeLancey JO, Center MM, Jemal A, Ward EM.
The global burden of cancer: priorities for prevention. Carcinogenesis. 2010;31:100-10. PMID:19934210.
13 Kobayashi H, Sendo F, Shirai T, Kaji H, Kodama T. Modification in growth of transplantable rat tumors exposed to Friend
virus. J Natl Cancer Inst. 1969;42:413-9. PMID: 5777490.
14 Itaya T, Yamagiwa S, Okada F, Oikawa T, Kuzumaki N,
Takeichi N, et al. Xenogenization of a mouse lung carcinoma (3LL) by transfection with an allogeneic class I major
histocompatibility complex gene (H-2Ld). Cancer Res.
1987;47:3136-40. PMID: 3107804.
15 Ishikawa M, Okada F, Hamada J, Hosokawa M, Kobayashi H.
Changes in the tumorigenic and metastatic properties of tu-

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