Next Article in Journal
ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish
Next Article in Special Issue
Prevention of Colorectal Cancer by Targeting Obesity-Related Disorders and Inflammation
Previous Article in Journal
One Year Follow-Up Risk Assessment in SKH-1 Mice and Wounds Treated with an Argon Plasma Jet
Previous Article in Special Issue
Impact of Acetazolamide, a Carbonic Anhydrase Inhibitor, on the Development of Intestinal Polyps in Min Mice
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction

Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan
Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(4), 867;
Submission received: 31 March 2017 / Revised: 14 April 2017 / Accepted: 17 April 2017 / Published: 19 April 2017
(This article belongs to the Special Issue Inflammation and Cancer)


A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.

1. Introduction

In 1863, Rudolf Virchow hypothesized that cancers occurred at sites of chronic inflammation [1]. This hypothesis has been confirmed by epidemiological and experimental pathological studies. Parkin showed that infection-related inflammation contributed to approximately 20% of all cancer cases worldwide [2]. Inflammation-inducible factors, such as air pollution, foreign bodies and ultraviolet radiation, are also associated with carcinogenesis [3].
Since chronic inflammation is associated with more than one-fifth of cancer incidence, there is an urgent need to explore chemopreventive agents against inflammation-related carcinogenesis. Before clinical trials of such agents are initiated, it is necessary to understand the pathogenesis of inflammation-related carcinogenesis by using animal models [4]. For example, rodent models for Helicobacter pylori and inflammatory bowel disease, which are the major causes of human gastric and colon cancers, respectively, have been developed to elucidate the underlying pathogenic mechanisms [4,5]. Epidemiological studies have shown that chronic inflammation predisposes individuals to various cancers, including cancer of the gastrointestinal tract [6]. Therefore, the use of agents targeted against inflammatory mediators might be a promising approach to prevent various types of inflammation-related cancers. To date, food products, natural compounds and synthetic low-molecular-weight compounds have been shown to suppress inflammation-related carcinogenesis. In this review, we summarize the mechanisms of inflammation-induced carcinogenesis by classifying the mechanisms of action of chemopreventive agents, and we propose 10 strategies for the prevention of carcinogenesis.

2. Causes of Inflammation-Related Carcinogenesis

The International Agency for Research on Cancer (IARC), through its IARC Monographs Programme, has performed carcinogenic hazard assessment of agents in humans based on experimental and clinical reports [7]. In this assessment, agents are classified into five groups (Group 1, 2A, 2B, 3 and 4). Group 1 carcinogens are those that are definitely carcinogenic to humans (Table 1). Table 1 also summarizes presumed carcinogenic agents classified into Group 2A to 3, as well as other previously-reported presumed carcinogenic agents not included in the IARC study.
Chronic inflammation increases the risk of human cancers of almost all organs/tissues (Figure 1); however, some chronic inflammatory conditions (e.g., psoriasis and rheumatoid arthritis) are not associated with cancers. Figure 2a,b shows infection by viruses, bacteria and parasites as a percentage of all of the causes of inflammation-related cancers; this percentage is 81% for definitely carcinogenic agents and 64% for presumed carcinogenic agents. Readers should refer to other review articles for comprehensive information regarding viral, bacterial or parasitic infection-induced cancers [68,69,70]. It has recently been realized that inhalation of airborne particles (foreign body) is a novel cause of cancer. Here, we focus on this new cause of cancer, i.e., foreign body-induced carcinogenesis.

Inhaled Foreign Body-Induced Carcinogenesis

A well-known carcinogenic foreign body is inhaled asbestos fibers, which are associated with mesothelioma and lung cancer (Table 1). The word “asbestos” is of Greek origin, being derived from “a”, meaning “not”, and “sbestos”, meaning “extinguishable”. Indeed, macrophages cannot remove the non-digestible asbestos fibers that lead to chronic inflammation [71].
There are three possible mechanisms for asbestos-induced carcinogenesis: (i) through the phenomenon of frustrated phagocytosis in which macrophages fail to phagocytose the long asbestos fibers and die with a massive release of reactive oxygen species (ROS) and pro-inflammatory cytokines that further induce chronic inflammation [72,73,74]; (ii) through asbestos-associated hemoglobin iron production of ROS via the Fenton reaction. This ROS damages DNA and stimulates the proliferation of alveolar epithelial cells and mesothelial cells [75]; and (iii) through asbestos induction of DNA double-stranded breaks in mesothelial cells, which leads to the promotion of genomic instability [73].
There was a general warning in 1973 that inhalation of asbestos causes lung cancer, gastrointestinal tract cancer and mesotheliomas [71]. The use of asbestos has since been banned in most developed countries; however, China and India still permit its usage [73]. Considering the latent period of mesothelioma (20 to 40 years after the first exposure to asbestos), its incidence is expected to increase further in the countries in which the peak of asbestos use was reached after the 1970s [71].
Not only manufactured products such as asbestos, but also airborne particles induce cancer. PM2.5 (particles with a diameter of 2.5 μm or less) can penetrate deeply into the lung, irritate and corrode the alveolar wall and lead to neutrophil infiltration [76]. Additionally, such gaseous particles were shown to decrease pulmonary function in schoolchildren [77]. This effect was caused by their induction of the overproduction of interleukin (IL)-8, an inflammatory cytokine [78]. Asian dust (AD) originates in China and transports a large amount of particulate matter to East Asian countries, such as Korea and Japan. In these countries, exposure to AD is associated with a decrease in the pulmonary function of adult patients with asthma or with asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome [79]. The mechanisms of the toxicity of PM2.5 towards the respiratory system have been investigated. These studies show that the environmental particle itself acts as a chronic inflammatory agent due to its low clearance rate and high deposition efficiency. In addition, the PM2.5 surface is rich in metals including ferrous iron, copper, zinc and manganese, as well as in polycyclic aromatic hydrocarbons and lipopolysaccharide, which are derived from power generation, industrial activity and biomass burning. These components can induce an inflammatory reaction [76]. An epidemiological study indicated that each 10 μg/m3 increase in PM2.5 was associated with a 19–30% increase in lung cancer mortality (Table 1) [80]. Considering the cross-border nature of airborne particles, international efforts to improve air quality are needed.
Air pollutants also originate from domestic heating and cooking with poor ventilation [16]. Cigarette smoke is another common air pollutant, as well as a foreign body. Smoking is the primary risk factor for COPD, which is characterized by chronic lung inflammation [81]. The presence of COPD is associated with six-times the risk for the development of lung cancer compared to smokers without COPD, indicating that COPD is an independent risk factor for lung cancer (Table 1) [82].

3. Animal Models for Inflammation-Related Cancer Chemoprevention Studies

Chemoprevention is the use of pharmacological or natural agents that inhibit or delay the development of cancer [83]. Various animal models that resemble human inflammation-related cancers have been previously generated by genetic engineering or by bacterial/chemical induction, and cancer prevention research has been facilitated by the use of those models (Table 2). We review these animal models in this section.

3.1. Esophageal Cancer

The rat model for esophago-duodenal anastomosis is known to sequentially progress from reflux esophagitis to Barrett’s esophagus and then to esophageal adenocarcinoma within 50 weeks of the operation [84]. Mouse reflux models yield a lower incidence of adenocarcinoma (7%) compared to rat models (40%) [95,96,97]. The rat reflux model is therefore widely used for the exploration of chemopreventive agents.

3.2. Gastric Cancer

Transgenic mice that overexpressed human gastrin and were infected with Helicobacter pylori (H. pylori) uniformly developed gastric adenocarcinoma by 24 weeks [98]. However, there have been no descriptions of non-genetically engineered mice that have developed gastric adenocarcinoma, which is probably a reflection of poor host adaptation to H. pylori [99]. Helicobacter felis (H. felis) isolated from the feline stomach can colonize the murine stomach similar to H. pylori and sequentially induce chronic gastritis, atrophy, intestinal metaplasia and adenocarcinoma [99,100]. However, unlike H. pylori infection of humans, neutrophil infiltration is less prominent in H. felis-induced murine gastritis, and H. felis is deficient in the production of the Helicobacter cytotoxin, vacA and the pro-inflammatory cytokine inducer, cagA [99,101]. Mice infected with H. pylori have a low susceptibility to gastric carcinogenesis even when a chemical carcinogen is used [102]. Besides these mouse models, a Mongolian gerbil was successfully established to mimic human H. pylori infection and chronic inflammation, in which the bacteria were detectable throughout the one-year study period [100]. Gastric adenocarcinomas that are very similar to those in humans were developed in 64% of H. pylori-infected Mongolian gerbils treated with N-methyl-N′-nitro-N-nitrosoguanidine at Week 50 [85].

3.3. Colon Cancer

Oral administration of dextran sulfate sodium (DSS) is well known to induce colitis in animals. DSS causes defects in epithelial barrier integrity, thereby enhancing colonic mucosal permeability to allow the entry of luminal antigens and bacteria into the mucosa, resulting in an inflammatory response [103]. Repeated administration of DSS that mimics acute and chronic phases of human ulcerative colitis induces chronic inflammation that is characterized by severe tissue injury of both the lamina propria and submucosa [103,104,105]. The use of DSS in combination with intraperitoneal injection of azoxymethane (AOM), a chemical carcinogen, results in 100% incidence of colonic tumors, whereas the incidence is only 13% to 19% when DSS is administered alone [86]. The incidence of neoplasia is also increased by administration of DSS in combination with other carcinogens, such as dimethylhydrazine (DMH) or 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine [86,87].
Genetically-modified animal models of colon cancer have been generated. For example, the ApcMin/+ mouse carries a germline mutation that converts codon 850 of the murine Adenomatous polyposis coli (Apc) gene from a leucine to a stop codon [106] and that mimics the development of adenomatous polyps in humans with familial adenomatous polyposis (FAP). However, the most common sites of tumors of ApcMin/+ mice is the small intestine [87]. ApcMin/+ mice exhibited adenomas in the small intestine at the age of five weeks [107] and subsequently developed intestinal adenomas (100% incidence). In the colon, precancerous lesions such as aberrant crypt foci or β-catenin accumulated crypts are observed, but the incidence of adenocarcinoma is no more than about 20% [108]. DSS administration to ApcMin/+ mice leads to colonic adenocarcinoma formation in all cases [87,108]. Since ApcMin/+ mice are Apc gene hetero-deficient, they are already in the initiated phase of tumor development. Therefore, DSS-induced inflammation acts as a promoter for colonic adenocarcinoma development [87].

3.4. Hepatocellular Carcinoma

Reliable methods to induce chronic inflammation-related hepatocellular carcinoma (HCC) in rodents are the use of chemicals or of transgenic approaches.
Hepatitis B or C viruses (HBV or HCV) can infect human hepatocytes subsequently leading to chronic inflammation and HCC development. In contrast to humans, mice are resistant to infection with HBV and HCV [109]. Transgenic mice carrying the full HBV genome except for the core protein were initially developed to model chronic HBV infection; however, HCC did not develop [110]. After this first report in 1985, transgenic mice overexpressing the HBV surface antigen in hepatocytes were established. This model exhibits chronic inflammation with necrosis, which inevitably leads to HCC [88].
Fourteen kinds of transgenic mice carrying HCV genes, such as the HCV polyprotein, and core protein alone or in combination with envelope proteins have been previously generated [109]. However, these HCV infection models either developed HCC without inflammation or did not form carcinomas [111]. Considering that there are no mouse models for hepatitis C-associated chronic inflammation-induced HCC, HBV transgenic mice are suitable as a mouse model that mimics the chronic carrier state of cancer-prone hepatitis virus infection.
Chemical carcinogens are also widely used to initiate hepatocarcinogenesis in animals. Diethylnitrosamine (DEN) was found to induce HCC in rodents in 1966 [112]. DEN is converted into a DNA alkylating agent by cytochrome P450 of hepatocytes and acts as a complete carcinogen if intraperitoneally injected into two-week-old mice [109]. The metabolic activation of DEN also generates ROS [109]. However, single injection of DEN results in carcinoma formation without cirrhosis. Therefore, the pathological process of the DEN-elicited rodent HCC is different from that of human HCC. In 2005, a rat model of DEN-induced liver injury that reproduces the sequence of cirrhosis and HCC that is observed in humans was established [89]. Once-a-week intraperitoneal injection of DEN for 16 weeks causes cirrhosis and multifocal HCC in all rats, similar to the case in human HCC [89].
Intraperitoneal injection of carbon tetrachloride (CCl4) induces pericentral necrosis of hepatocytes and inflammatory cell infiltration. In CCl4 treatment alone, only 25% of mice showed HCC [90]. In contrast, HCC was found in 50% of mice when a single injection of DEN, functioning as a tumor initiator, was followed by repeat treatment with CCl4, used as a tumor promoter, for 14 weeks.

3.5. Cholangiocarcinoma

Syrian golden hamsters infested with the liver fluke, Opisthorchis viverrini (O. viverrini), have been used as a model for cholangiocarcinoma. Infestation of the liver fluke alone rarely leads to cholangiocarcinoma. However, 100% incidence of bile duct cancers resembling those seen in humans resulted from the infestation prior to administration of N-nitrosodimethylamine (NDMA) [91]. The effect of liver fluke infestation and NDMA dose on the development of bile duct cancer is synergistic [113], indicating that there are several mechanisms underlying infestation-related carcinogenesis [114]. Firstly, the presence of the parasite mechanically damages bile duct epithelial cells that have a mutation that is caused by the carcinogen, resulting in increased cell proliferation, which fixes the DNA mutation [115,116]. Secondary, ROS and nitric oxide (NO) released by inflammatory cells cause DNA damage [114,117]. The third possibility is that inflammatory cells produce pro-inflammatory cytokines [114]. A fourth possible explanation is that O. viverrini secretes exosomes, one kind of membrane vesicle containing proteins, mRNA, miRNAs and DNAs [118], to promote cholangiocyte proliferation and IL-6 production [119].

3.6. Biliary Tract Cancer

Pancreaticobiliary maljunction (PBM) is characterized by abnormal fusion of the pancreatic and biliary ducts [120]. A PBM model was developed using the Syrian golden hamster [121]. Cholecystoduodenostomy in hamsters causes reflux of pancreatic juice into the biliary tract; as a result, pancreatic enzymes and secondary bile acid induce chronic inflammation with injury to biliary epithelia [122]. Biliary tract cancer developed in 41% to 82% of N-nitrosobis(2-oxopropyl)amine subcutaneously-injected hamsters after cholecystoduodenostomy [92].

3.7. Pancreatic Ductal Adenocarcinoma

Approximately 90% of human pancreatic ductal adenocarcinomas (PDAC) harbor mutations in codon 12, 13 or 61 of the K-ras gene [123,124], suggesting that K-ras is a driver gene in PDAC. However, only 50% of transgenic mice carrying a mutation of codon 12 of the K-ras allele (K-ras-mutated mice) developed PDAC [93]. When caerulein, an inducer of pancreatitis, was intraperitoneally-injected into K-ras-mutated mice constantly for six months, all of the mice had PDAC [93]. This result shows that chronic pancreatitis is necessary for the induction of PDAC and that K-ras mutation alone is insufficient for pancreatic carcinogenesis.

3.8. Skin Cancer

Two-stage skin carcinogenesis was developed in the 1940s. In the first stage, initiation occurs following a single administration of 7,12-dimethylbenz[a]-anthracene (DMBA). In the second stage, benign papillomas and/or invasive squamous cell carcinomas (SCC) developed by repeated treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), an inflammatory agent, to the initiated skin [94]. The DMBA/TPA skin model is used for screening of cancer chemopreventive compounds [125]. DMBA generates a point mutation in Ha-ras. TPA stimulates inflammation and the proliferation of Ha-ras-mutated cells [94]. Papillomas developed in about 80% of the mice by 22 weeks after initiation; the frequency of conversion of papilloma to carcinoma was about 20% at Week 32 [126]. A whole-exome sequencing study showed that 18% to 44% of the genes in DMBA/TPA-induced SCC, including Ha-ras, K-ras and p53, overlapped with genes in human SCC [127]. The DMBA/TPA skin tumor model therefore mimics human skin carcinogenesis at the genetic level.

3.9. Experimental Models of Foreign Body-Induced Carcinogenesis

In addition to infection, administration of a chemical substance or implantation of a foreign body also induces inflammation-related carcinogenesis. The first experimental evidence for a foreign body-induced tumor was reported in 1941 [71]. Most animal models of foreign body-induced tumorigenesis do not require a chemical carcinogen.
For example, 79% heterozygous p53-deficient (p53+/−) mice developed spontaneous sarcomas via induction of p53 loss of heterozygosity at a mean time of 35 weeks after a piece of plastic plate (1 mm × 5 mm × 10 mm, polystyrene, used as a culture dish) was subcutaneously implanted [128]. Thus, an inflammatory reaction against a foreign body is sufficient for tumorigenesis. The carcinogenic potential of a foreign body depends on its properties [71]. Solid, smooth and large foreign bodies are more potent inducers of chronic inflammation than more roughened, smoothened and smaller ones [129]. As examples of foreign body-induced tumors, human or rodent immortalized cell lines that had been implanted attached to a plastic plate or a glass bead into mice or rats grew progressively in 8% to 100% of animals regardless of the origin of the cell (species, epithelial or non-epithelial cells) [71]. Another approach to establish this model is by using regressive tumors or precancerous cells.
FPCK-1-1 cells that are derived from a colonic polyp of a patient with FAP are non-tumorigenic when injected subcutaneously into nude mice. However, when these cells were attached to a piece of plastic plate and implanted into a subcutaneous space, the cells spontaneously converted into progressively-growing, moderately-differentiated adenocarcinoma cells in 65% of the mice [130]. The plastic plate initially induces acute inflammation, which then transitions to chronic inflammation [130]. A highly proliferative fibrous stroma composed mainly of fibroblasts was formed 120 days after plastic plate implantation. When FPCK-1-1 cells were injected into stromal tissues that were surrounded by a plastic plate, they converted into adenocarcinoma cells [130]. This result showed that the malignant conversion of FPCK-1-1 cells occurred not due to the plastic plate itself, but due to the plastic plate-induced fibrous stroma. NO derived from a chronically-inflamed lesion caused the conversion of FPCK-1-1 cells [131]. Moreover, the actin-filament bundling protein fascin-1 was found to be a suppressor of anoikis (apoptotic cell death as a consequence of insufficient cell-to-substrate interactions) and to drive the malignant conversion of FPCK-1-1 cells [132]. This malignant conversion seldom occurs in adenoma cells in the presence of a gelatin sponge, which is spontaneously absorbed in a short period and thus induces only the early phase of inflammation, indicating that the conversion requires chronic inflammation [130]. It should be noted that the carcinogenic inflammation was not induced in colon tissue, which is an orthotopic site for colon carcinogenesis, but in a subcutaneous space, which is an ectopic site. This evidence indicates that causes or sites of inflammation do not account for colon carcinogenesis, but that long-standing inflammation is necessary for colon carcinogenesis [130].
We have introduced chronic inflammation as a common cause of inflammation-related cancers in this review. However, acute inflammation also induces tumor formation experimentally. QR-32 cells (a mouse fibrosarcoma clone) regressed spontaneously after injection into syngeneic C57BL/6 mice, but could grow indefinitely in vitro [133]. Subcutaneous implantation of a gelatin sponge (3 mm × 5 mm × 10 mm) induces inflammatory cell (mainly neutrophils) infiltration. As mentioned above, the sponge is naturally absorbed about four weeks after implantation, and therefore, transition from acute to chronic inflammation is unlikely to occur when using a sponge [71]. The regressive QR-32 cells become tumorigenic after implantation into a pre-inserted piece of sponge. Moreover, the sponge-infiltrated inflammatory cells convert QR-32 cells into tumorigenic cells when both cells are mixed and injected subcutaneously [133]. Elimination of neutrophils by administration of an anti-neutrophil antibody inhibited the acquisition of malignant phenotype by QR-32 cells [134]. These findings show that neutrophil infiltration is needed for inflammation-related carcinogenesis [133,134]. There are advantages in using a gelatin sponge for investigating inflammation-related carcinogenesis. Since sponge-infiltrated inflammatory cells can be collected by treating the sponge with collagenase, it is possible to quantify the number of infiltrated cells, determine the cell types and analyze the molecular expression profiles of the inflammatory reaction [135].

4. Ten Mechanisms Involved in Inflammation-Related Carcinogenesis-Based Chemoprevention

Cancer prevention is the ultimate goal of inflammation-related carcinogenesis research. Chemoprevention research by using animal models of inflammation-related carcinogenesis as described above started in the late 1990s and continues to this day.
Chemopreventive agents act through a combination of various mechanisms. By the study of these mechanisms of action, we summarized 10 mechanisms that are involved in the promotion of inflammation-related cancer development. These mechanisms are: (i) inflammatory cell infiltration; (ii) ROS; (iii) NO; (iv) reduction of antioxidant enzymes; (v) reduction of antioxidants; (vi) activation of NF-κB; (vii) upregulation of pro-inflammatory cytokines; (viii) downregulation of anti-inflammatory cytokines; (ix) elevation of chemokines; and (x) induction of cyclooxygenase (COX)-2 (Figure 3).

4.1. Inflammatory Cell Infiltration

Tissue injury caused by factors such as infection or a foreign body induces the sequential infiltration of neutrophils and monocytes (Figure 3). Granulocyte macrophage colony-stimulating factor released from epithelial cells or fibroblasts induces the differentiation of monocytes into M1 macrophages [136]. IL-4 works with macrophage colony-stimulating factor to induce to M2 macrophage polarization [137]. Tumor-associated macrophages (M2-like macrophages) promote inflammation-related carcinogenesis [138]. Infiltrated (activated) neutrophils, but not circulating or bone marrow neutrophils, are involved in carcinogenesis [133,134]. Depletion of macrophages using clodronate inhibited macrophage infiltration, resulting in suppression of AOM/DSS-induced mouse colon carcinogenesis [139]. Therefore, not only neutrophils, but also macrophages are necessary for cancer development in chronic inflammatory conditions. Indeed, the number of myeloperoxidase-positive cells (neutrophils and macrophages) was higher in the colonic mucosa of patients with inflammatory bowel disease (IBD) or its associated cancer than in normal mucosa [140], suggesting that inflammatory cell infiltration also plays a key role in human carcinogenesis.
Chemokines and adhesion molecules function in the recruitment of neutrophils and monocyte into inflammatory sites [141]. Integrin β2 is the key adhesion molecule for neutrophil extravasation. C-C motif chemokine receptor (CCR)2 is a specific receptor for the monocyte-tropic chemokine, C-C motif chemokine ligand (CCL)2. Genetic deletion of integrin β2 or CCR2 inhibited neutrophil/monocyte infiltration and protected mice from inflammation-related carcinogenesis [134,142]. Thus, inhibition of the initial process of inflammation, i.e., the infiltration of inflammatory cells, is a target for the prevention of chronic inflammation and carcinogenesis (Table 3).

4.2. Reactive Oxygen Species

Oxidative stress can lead to mutations and increased cell proliferation, and therefore, it plays a crucial role in inflammation-related carcinogenesis.
High ROS accumulation results in oxidative damage to DNA, protein or lipids, while a small increase in ROS acts as a growth signaling molecule in both normal and cancer cells [212]. Moreover, ROS is mutagenic across species [213]. In acute inflammation, the infiltrated inflammatory cells generate a massive amount of ROS to kill the invading pathogens [214,215]. If the acute inflammatory response fails to eliminate the pathogens and the inflammatory process persists, the sustained overproduction of ROS induces DNA damage and the proliferation of normal cells, which are associated with an increased risk of neoplastic transformation [214].
The bactericidal function of phagocytes including neutrophils depends on the generation of superoxide from the NADPH oxidase complex, which consists of cytosolic proteins (gp40phox, gp47phox, gp67phox and Rac) and a membrane-bound complex carrying cytochrome b558 (gp91phox, the catalytic core of phagocyte NADPH oxidase and gp22phox) [216,217]. In gp91phox−/− mice, inflammation-related tumor development and metastasis were suppressed. Adoptively-transferred wild-type-derived infiltrated phagocytes into gp91phox−/− mice recovered the acquisition of tumorigenicity and metastatic potential [218].
ROS further generates other reactive species (e.g., malondialdehydes (MDA) and 4-hydroxynonenal (4-HNE)) through lipid peroxidation. MDA and 4-HNE induce point mutation of the proto-oncogene K-ras and the tumor suppresser gene p53 (Figure 3), thereby acting as a driving force for malignancy in chronic pancreatitis and IBD [219].

4.3. Nitric Oxide

NO is also released from infiltrated cells in chronic inflammatory tissues and causes alterations in DNA. NO is involved in colon cancer [220] and esophageal cancer [221] associated with inflammation. The main mechanisms of ROS and NO in inflammation-related carcinogenesis are DNA base modifications and strand breaks resulting in DNA-replication errors and genomic instability (Figure 3) [214]. There are at least two mechanism of NO-mediated carcinogenesis. First, NO converts colonic adenoma cells to adenocarcinoma cells by inducing the acquisition of resistance to anoikis [131]. Second, NO inactivates DNA repair enzymes and p53 proteins via post-translational modifications, such as nitrosylation, nitration and deamination (Figure 3) [222].

4.4. Reduction of Antioxidant Enzymes

The ROS level is determined by the rates of both ROS production and of ROS scavenging [212]. Therefore, suppression of the ROS production system or promotion of ROS scavenging activity is an effective strategy to prevent carcinogenesis.
In an experimental inflammation-related tumorigenesis model, an inverse correlation was observed between the frequency of inflammatory cell-induced somatic mutation or tumor formation and the activity of intracellular antioxidant enzymes (manganese superoxide dismutase (Mn-SOD) and glutathione peroxidase) [223]. Moreover, treatment with polysaccharide K [177] or an orally-available SOD [176] suppressed inflammation-related tumorigenesis by increasing Mn-SOD via induction of inflammatory cytokines.

4.5. Reduction of Antioxidant

Free radicals have an unpaired electron. Antioxidant vitamins C and E donate an electron to a free radical, thereby scavenging it. These antioxidant vitamins inhibit lipid peroxidation and nitration of tyrosine residues of proteins [224,225,226,227]. An epidemiological study showed that high intakes of vitamins C and E exhibited inverse associations with gastric cancer in H. pylori-infected subjects compared with non-infected individuals [228]. γ-Tocopherol, a major form of vitamin E, when present at 0.1% in the diet decreased the number of adenomatous polyps by 85% in the AOM/DSS colon cancer model [179]. Thus, the preventive effect of antioxidants on inflammation-related carcinogenesis has been observed both in human studies and in animal experiments.

4.6. Activation of NF-κB

NF-κB (a heterodimer of p50/NF-κB1 and p65/RelA) is found in the cytoplasm where it is bound to IκBs that prevent its activation in unstimulated cells. IκB phosphorylation causes its ubiquitin-proteasomal degradation, leading to the release of NF-κB, which then enters the nucleus and functions as a transcription factor of inflammation-related genes [229].
NF-κB has been found to be constitutively activated in inflammatory diseases, such as IBD and COPD [230,231]. Its activation is induced by pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, IL-1β, IL-6 and IL-8), ROS, bacterial infection and ultraviolet irradiation [229,232]. NF-κB promotes the transcription of pro-inflammatory cytokines, leukocyte chemoattractant proteins (chemokine (C-X-C motif) ligand (CXCL)12, CCL2 and CCL3), COX-2 and endothelial adhesion molecules (E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1), leading to enhancement of inflammatory cell infiltration and inflammatory reactions [232,233]. NF-κB activation also increases the expression of ROS-producing enzymes (gp91phox, xanthine oxidase) or inducible NO synthase (Figure 3), resulting in the promotion of cell proliferation, the acquisition of apoptosis resistance and induction of genetic instability [214,234,235].
A recent report showed that NF-κB promoted TNF-α secretion, which, in turn, activated more NF-κB, in acute myeloid leukemia [236]. This NF-κB/TNF-α positive feedback loop also exists in inflammation associated with Barrett’s carcinogenesis [237], indicating that it is a common mechanism in both epithelium and non-epithelium. Inflammation-related cancer development may be suppressed by any one of the inhibitions of NF-κB activation, downregulation of pro-inflammatory cytokines or upregulation of an anti-inflammatory cytokine (IL-10) due to breakdown of the NF-κB/TNF-α positive feedback loop.

4.7. Upregulation of Pro-Inflammatory Cytokines

Pro-inflammatory cytokines (e.g., IL-1β, IL-6 and TNF-α) are produced by macrophages, B and T lymphocytes, endothelial cells and fibroblasts. These cytokines exert paracrine and autocrine effects via binding to their transmembrane receptors [238,239,240]. These cytokines are involved in the promotion of cell proliferation, induction of angiogenesis, autophagy and inhibition of apoptosis [238]. In the DMBA/TPA skin tumor model, 100% of wild-type mice had tumors (7.3 tumors per mouse). In contrast, only 38% of TNF-α-null mice developed tumors (0.9 tumors per mouse) because keratinocyte hyperproliferation and inflammation were diminished by deletion of TNF-α [241].
TNF-α and interferon-γ induce autophagy, a cellular degradation process involving the amino acid recycling for cellular survival and proliferation [160,242]. Melatonin prevents the development of adenocarcinoma by suppressing of autophagy in DMH/DSS colon cancer model [160].
The inflammasome is a multi-protein complex functioning as a platform for the activation of caspase-1, which then lead to the maturation of IL-1β and IL-18 [243,244]. The activation of the inflammasome in immune cells (dendritic cells and macrophages) increases the recruitment of suppressive immune cells, such as myeloid-derived suppressor cells and regulatory T cells and facilitates angiogenesis through the release of fibroblast growth factor-2 and vascular endothelial growth factor [245].
Epidermal growth factor (EGF) is secreted by platelets and macrophages [246], and its expression is increased in inflammatory diseases and at wound sites [247,248]. To examine the effect of EGF on the tumor progression of weakly-tumorigenic and nonmetastatic rat mammary adenocarcinoma (ER-1) cells, the cells were exposed to EGF (100 ng/mL) for a short (24 h) or a long (one month) period in vitro [249]. Each EGF treatment period converted ER-1 cells into tumorigenic and metastatic cells. Their malignant features were reversible during the short exposure to EGF, but the acquired malignant phenotypes were fixed by long exposure. The acquisition of malignant phenotypes was prevented by the addition of an antioxidant, N-acetylcysteine or selenium [182,249]. It is therefore assumed that EGF that is present in an inflammatory environment stimulates ROS production, resulting in oxidative DNA damage and malignant conversion.

4.8. Downregulation of Anti-Inflammatory Cytokines

Anti-inflammatory cytokines such as IL-10 are produced by CD8+ T cells [250]. IL-10 inhibits NF-κB signaling at two levels: (i) through blocking of the activity of IκB kinases and (ii) through inhibition of NF-κB DNA binding [251]. All IL-10-deficient mice spontaneously developed colitis at the age of nine weeks. In 10 to 31-week-old mice, the incidence of colorectal adenocarcinomas reached 65% [252]. IL-10 has anti-inflammatory and then anti-tumorigenic properties, since it suppress levels of IL-6 and TNF-α [239].

4.9. Elevation of Chemokines

Chemokines recruit leukocytes into inflammatory sites. A high serum level of CXCL13, a B-cell chemoattractant, was associated with poor prognosis, bone marrow invasion and the presence of Epstein-Barr virus DNA in non-Hodgkin lymphoma patients [253]. In addition to CXCL13, the expression level of CCL2, a monocyte chemoattractant, was 30- to 50-times higher in the colonic mucosa from patients with ulcerative colitis and Crohn’s disease than in that from controls [254]. CCL2 overexpression was also observed in the AOM/DSS colitis-associated carcinoma model [142]. The enhanced intracolonic macrophage infiltration and tumor development in this model were suppressed by using mice deficient in the CCL2-specific receptor, CCR2 [142]. Inhibition of chemokines decreases inflammatory cell infiltration and eventually attenuates carcinogenesis.

4.10. Induction of Cyclooxygenase-2

Prostaglandin E (PGE)2 is synthesized in multiple-steps: first, arachidonic acid is released from membrane-bound phospholipids by phospholipase A2; next, arachidonic acid conversion to prostaglandin H2 is mediated by COX; finally, PGE2 is produced by PGE synthase [255,256]. PGE2 causes increased cell proliferation, inhibition of apoptosis, stimulation of angiogenesis and immunosuppression in various cancers (Figure 3) [257]. In 1897, Hoffmann synthesized aspirin, a nonsteroidal anti-inflammatory drug (NSAID). Vane was the first to show that the active mechanism of aspirin was that of an inhibitor of COX [258]. The IARC evaluates NSAIDs, such as aspirin and sulindac, as cancer chemopreventive agents [259]. A clinical trial in the United Kingdom indicated that the use of aspirin for about five years was effective in the prevention of colon cancer [260]. In addition to colon cancer, a chemopreventive effect of aspirin and other NSAIDs has also been reported for esophageal, gastric, lung, breast and prostate cancers [261]. COX-2 is induced by an inflammatory stimulus (infection, a foreign body, alcohol or tobacco), whereas COX-1 is constitutively expressed in gastrointestinal epithelium, renal tubules and platelets [229,239,262]. The NSAIDs aspirin, diclofenac, ibuprofen, indomethacin, naproxen and piroxicam are nonselective inhibitors of COX isozymes, and therefore, they increase the risk of gastrointestinal events, including bleeding and ulcer [263,264]. Shortly after the first of those reports, selective COX-2 inhibitors (celecoxib, etodolac, meloxicam, rofecoxib) were developed in order to reduce adverse effects [263]. A case-control study suggests that NSAIDs including celecoxib and rofecoxib might reduce the risk of patients with Barrett’s esophagus developing esophageal adenocarcinoma [265].
Selective and nonselective COX-2 inhibitors (MF-Tricyclic and sulindac, respectively) lower PGE2 levels and inhibit esophagitis and the development of adenocarcinoma in a rat model of Barrett’s esophagus [211]. This cancer preventive effect was also shown in an H. pylori-infected gastric cancer model, the AOM/DSS-induced colon cancer model and a pancreatic cancer model using caerulein and K-ras mutated mice [192,210,266]. Besides NSAIDs, fermented brown rice, rice bran with Aspergillus oryzae [184] and methanol extracts from the fruit of A. communis and the leaf of A. communis [147] also prevent inflammation-related carcinogenesis of the colon or skin by decreasing COX-2 expression (Table 3).

5. Candidate Chemopreventive Agents against Inflammation-Related Carcinogenesis

Table 3 presents a summary of 79 candidate chemopreventive agents reported in 70 primary journal articles using the above-described animal models of inflammation-related carcinogenesis. The information sources for this review include PubMed (from 1996 to 2017, Available online:
These 79 agents are classified into five groups: 34 natural compounds; 16 food products; 14 low-molecular-weight compounds; 5 COX inhibitors; and 10 others. The first four groups account for 87% of the total number of isolated agents. The mechanisms of action of these groups are listed in Figure 4 and are classified into the ten above-described mechanisms involved in inflammation-related carcinogenesis. Natural compounds followed by food products have the highest number of mechanisms of action. In contrast, low-molecular-weight compounds and COX inhibitors have a much lower number of mechanisms of action. These findings indicate that natural compounds and food products prevent inflammation-related carcinogenesis more effectively than low-molecular-weight compounds and specific molecular-targeted inhibitors. Of note, food products are low-cost because they are not perceived as “medicine”, and they are safe for long-term administration [267,268]. Cancer cases/deaths due to infection (inflammation) are expected to increase rapidly in low-income and middle-income countries within the next few decades [269]. Therefore, food products with anticarcinogenic/antiphlogistic effects may be ideal for cancer prevention in those countries.

6. Future Prospects

Chronic inflammation is central and common to the pathogenesis of not only carcinogenesis, but also cardiovascular disorders (arteriosclerosis, polyarteritis nodosa, aortitis syndrome and myocarditis), autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease, type 1 diabetes, Hashimoto’s thyroiditis, Graves’ disease and sarcopenia), metabolic disorders (metabolic syndrome, type 2 diabetes and obesity) and neurological diseases (Alzheimer’s dementia, Parkinson’s disease and depression) [270,271,272,273,274,275,276,277,278,279,280,281,282,283]. Centenarians who are older than 100 years have higher levels of C-reactive protein, a sensitive indicator of inflammation, than younger people, indicating that chronic inflammation is also associated with healthy life expectancy [284]. The natural compounds and food products with preventive effects against inflammation-related cancers that are summarized in this review are expected to inhibit the above-listed inflammatory diseases because these agents have multiple inhibitory mechanisms of action.
Figure 1 shows that inflammation-related cancers develop in most organs/tissues. On the other hand, some inflammatory diseases do not increase cancer risk [285]; there has been no report showing that psoriasis or rheumatoid arthritis induces inflammation-related carcinogenesis. We assume two possible hypotheses for the difference in carcinogenic property between inflammatory diseases: (i) particular organs/tissues have resistance to carcinogenesis; (ii) the susceptibility of organs/tissues to carcinogenesis depends on the quality or the degree of the inflammatory reaction. Elucidation of these issues will lead to further understanding of the mechanism of inflammation-related carcinogenesis.


This work was supported in part by a Grant-in-Aid to Futoshi Okada from the Japanese Ministry of Education, Culture, Sports, Science and Technology; the Environmental Research and Technology Development Fund (5-1453) of the Japanese Ministry of the Environment; the Research Grant of the Princess Takamatsu Cancer Research Fund. This work was also supported in part by a Grant-in-Aid to Mitsuhiko Osaki from the Takeda Science Foundation; Yusuke Kanda was supported by the Japan Society for the Promotion of Science (Research Fellowship for Young Scientists).

Conflicts of Interest

The authors declare no conflict of interest.


ADAsian dust
ApcAdenomatous polyposis coli
ATLAdult T-cell leukemia
CCLC-C motif chemokine ligand
CCl4Carbon tetra chloride
COPDChronic obstructive pulmonary disease
CXCLChemokine (C-X-C motif) ligand
DLBCDiffuse large B-cell
DSSDextran sulfate sodium
EAPPEthanol extracts from the aerial parts of A. princeps Pampanini cv. Sajabal
EBVEpstein-Barr virus
EGFEpidermal growth factor
EVOOExtra virgin olive oil
FAPFamilial adenomatous polyposis
FBEFruiting body extract
FBRAFermented brown rice and rice bran with Aspergillus oryzae
GOFA/β-CD3-(4′-Geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid/β-cyclodextrin
GOFA-L-NAME4′-Geranyloxyferulic acid-N(omega)-nitro-l-arginine methyl ester
H. felisHelicobacter felis
H. pyloriHelicobacter pylori
HBVHepatitis B virus
HCCHepatocellular carcinoma
HCVHepatitis C virus
HDVHepatitis D virus
HERV-KHuman endogenous retrovirus type K
HIVHuman immunodeficiency virus
HPVHuman papillomavirus
HTLV-1Human T-cell lymphotropic virus type 1
IARCInternational Agency for Research on Cancer
IBDInflammatory bowel disease
iNOSInducible nitric oxide synthase
JCVJC virus
KSHVKaposi sarcoma herpes virus
MALTMucosa-associated lymphoid tissue
MCVMolluscum contagiosum virus
MEMycelia extract
MEFAMethanol extracts of the fruit of A. communis
MELAMethanol extract of the leaf of A. communis
Mn-SODManganese superoxide dismutase
NONitric oxide
NSAIDNonsteroidal anti-inflammatory drug
O. viverriniOpisthorchis viverrini
PAGProcessed Aloe vera gel
PBMPancreaticobiliary maljunction
PDACPancreatic ductal adenocarcinomas
PEITCPhenethyl isothiocyanate
PGEProstaglandin E
PhIP2-Amino-1-methyl-6-phenylimidazo[4,5-b] pyridine
PSKPolysaccharide K
ROSReactive oxygen species
SCCSquamous cell carcinoma
TNFTumor necrosis factor
UDCAUrsodeoxycholic acid
γ-TmTγ-Tocopherol-rich mixture of tocopherols
13-HOA(±)-13-Hydroxy-10-oxo-trans-11-octadecenoic acid


  1. Balkwill, F.; Mantovani, A. Inflammation and cancer: Back to Virchow? Lancet 2001, 357, 539–545. [Google Scholar] [CrossRef]
  2. Parkin, D.M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 2006, 118, 3030–3044. [Google Scholar] [CrossRef] [PubMed]
  3. Belpomme, D.; Irigaray, P.; Hardell, L.; Clapp, R.; Montagnier, L.; Epstein, S.; Sasco, A.J. The multitude and diversity of environmental carcinogens. Environ. Res. 2007, 105, 414–429. [Google Scholar] [CrossRef] [PubMed]
  4. Lu, L.; Chan, R.L.; Luo, X.M.; Wu, W.K.; Shin, V.Y.; Cho, C.H. Animal models of gastrointestinal inflammation and cancer. Life Sci. 2014, 108, 1–6. [Google Scholar] [CrossRef] [PubMed]
  5. Maeda, S.; Omata, M. Inflammation and cancer: Role of nuclear factor-κB activation. Cancer Sci. 2008, 99, 836–842. [Google Scholar] [CrossRef] [PubMed]
  6. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444. [Google Scholar] [CrossRef] [PubMed]
  7. Ostry, V.; Malir, F.; Toman, J.; Grosse, Y. Mycotoxins as human carcinogens-the IARC Monographs classification. Mycotoxin Res. 2017, 33, 65–73. [Google Scholar] [CrossRef] [PubMed]
  8. Cogliano, V.J.; Baan, R.; Straif, K.; Grosse, Y.; Lauby-Secretan, B.; El Ghissassi, F.; Bouvard, V.; Benbrahim-Tallaa, L.; Guha, N.; Freeman, C.; et al. Preventable exposures associated with human cancers. J. Natl. Cancer Inst. 2011, 103, 1827–1839. [Google Scholar] [CrossRef] [PubMed]
  9. Elinav, E.; Nowarski, R.; Thaiss, C.A.; Hu, B.; Jin, C.; Flavell, R.A. Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 2013, 13, 759–771. [Google Scholar] [CrossRef] [PubMed]
  10. Ohshima, H.; Miyoshi, N.; Tomono, S. Infection, Inflammation, and Cancer: Overview. In Cancer and Inflammation Mechanisms; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2014; pp. 1–7. [Google Scholar]
  11. Wen, B.W.; Tsai, C.S.; Lin, C.L.; Chang, Y.J.; Lee, C.F.; Hsu, C.H.; Kao, C.H. Cancer risk among gingivitis and periodontitis patients: A nationwide cohort study. QJM 2014, 107, 283–290. [Google Scholar] [CrossRef] [PubMed]
  12. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr. Eval. Carcinog. Risks Hum. 2012, 100, 1–441. [Google Scholar]
  13. Siirala, U. Tongue cancer. Acta Otolaryngol. 1973, 75, 309. [Google Scholar] [CrossRef] [PubMed]
  14. Lee, J.H.; Kim, Y.; Choi, J.W.; Kim, Y.S. The association between papillary thyroid carcinoma and histologically proven Hashimoto’s thyroiditis: A meta-analysis. Eur. J. Endocrinol. 2013, 168, 343–349. [Google Scholar] [CrossRef] [PubMed]
  15. Muto, M.; Hitomi, Y.; Ohtsu, A.; Shimada, H.; Kashiwase, Y.; Sasaki, H.; Yoshida, S.; Esumi, H. Acetaldehyde production by non-pathogenic Neisseria in human oral microflora: Implications for carcinogenesis in upper aerodigestive tract. Int. J. Cancer 2000, 88, 342–350. [Google Scholar] [CrossRef]
  16. Loomis, D.; Grosse, Y.; Lauby-Secretan, B.; El Ghissassi, F.; Bouvard, V.; Benbrahim-Tallaa, L.; Guha, N.; Baan, R.; Mattock, H.; Straif, K.; et al. The carcinogenicity of outdoor air pollution. Lancet Oncol. 2013, 14, 1262–1263. [Google Scholar] [CrossRef]
  17. Santillan, A.A.; Camargo, C.A., Jr.; Colditz, G.A. A meta-analysis of asthma and risk of lung cancer (United States). Cancer Causes Control 2003, 14, 327–334. [Google Scholar] [CrossRef] [PubMed]
  18. Houghton, A.M. Mechanistic links between COPD and lung cancer. Nat. Rev. Cancer 2013, 13, 233–245. [Google Scholar] [CrossRef] [PubMed]
  19. Matsushita, H.; Tanaka, S.; Saiki, Y.; Hara, M.; Nakata, K.; Tanimura, S.; Banba, J. Lung cancer associated with usual interstitial pneumonia. Pathol. Int. 1995, 45, 925–932. [Google Scholar] [CrossRef] [PubMed]
  20. Yamaguchi, M.; Odaka, M.; Hosoda, Y.; Iwai, K.; Tachibana, T. Excess death of lung cancer among sarcoidosis patients. Sarcoidosis 1991, 8, 51–55. [Google Scholar] [PubMed]
  21. Wu, C.Y.; Hu, H.Y.; Pu, C.Y.; Huang, N.; Shen, H.C.; Li, C.P.; Chou, Y.J. Pulmonary tuberculosis increases the risk of lung cancer: A population-based cohort study. Cancer 2011, 117, 618–624. [Google Scholar] [CrossRef] [PubMed]
  22. Zhan, P.; Suo, L.J.; Qian, Q.; Shen, X.K.; Qiu, L.X.; Yu, L.K.; Song, Y. Chlamydia pneumoniae infection and lung cancer risk: A meta-analysis. Eur. J. Cancer 2011, 47, 742–747. [Google Scholar] [CrossRef] [PubMed]
  23. Ragin, C.; Obikoya-Malomo, M.; Kim, S.; Chen, Z.; Flores-Obando, R.; Gibbs, D.; Koriyama, C.; Aguayo, F.; Koshiol, J.; Caporaso, N.E.; et al. HPV-associated lung cancers: An international pooled analysis. Carcinogenesis 2014, 35, 1267–1275. [Google Scholar] [CrossRef] [PubMed]
  24. Kirk, G.D.; Merlo, C.; O’Driscoll, P.; Mehta, S.H.; Galai, N.; Vlahov, D.; Samet, J.; Engels, E.A. HIV infection is associated with an increased risk for lung cancer, independent of smoking. Clin. Infect. Dis. 2007, 45, 103–110. [Google Scholar] [CrossRef] [PubMed]
  25. Steenland, K.; Stayner, L. Silica, asbestos, man-made mineral fibers, and cancer. Cancer Causes Control 1997, 8, 491–503. [Google Scholar] [CrossRef] [PubMed]
  26. Salmons, B.; Lawson, J.S.; Gunzburg, W.H. Recent developments linking retroviruses to human breast cancer: Infectious agent, enemy within or both? J. Gen. Virol. 2014, 95, 2589–2593. [Google Scholar] [CrossRef] [PubMed]
  27. Grabowski, J.; Wedemeyer, H. Hepatitis delta: Immunopathogenesis and clinical challenges. Dig. Dis. 2010, 28, 133–138. [Google Scholar] [CrossRef] [PubMed]
  28. Abdel-Hamid, N.M. Recent insights on risk factors of hepatocellular carcinoma. World J. Hepatol. 2009, 1, 3–7. [Google Scholar] [CrossRef] [PubMed]
  29. Singh, S.; Talwalkar, J.A. Primary sclerosing cholangitis: Diagnosis, prognosis, and management. Clin. Gastroenterol. Hepatol. 2013, 11, 898–907. [Google Scholar] [CrossRef] [PubMed]
  30. Kamisawa, T.; Kuruma, S.; Chiba, K.; Tabata, T.; Koizumi, S.; Kikuyama, M. Biliary carcinogenesis in pancreaticobiliary maljunction. J. Gastroenterol. 2017, 52, 158–163. [Google Scholar] [CrossRef] [PubMed]
  31. Scanu, T.; Spaapen, R.M.; Bakker, J.M.; Pratap, C.B.; Wu, L.E.; Hofland, I.; Broeks, A.; Shukla, V.K.; Kumar, M.; Janssen, H.; et al. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host Microbe 2015, 17, 763–774. [Google Scholar] [CrossRef] [PubMed]
  32. Weiss, F.U. Pancreatic cancer risk in hereditary pancreatitis. Front. Physiol. 2014, 5, 70. [Google Scholar] [CrossRef] [PubMed]
  33. Zheng, W.; McLaughlin, J.K.; Gridley, G.; Bjelke, E.; Schuman, L.M.; Silverman, D.T.; Wacholder, S.; Co-Chien, H.T.; Blot, W.J.; Fraumeni, J.F., Jr. A cohort study of smoking, alcohol consumption, and dietary factors for pancreatic cancer (United States). Cancer Causes Control 1993, 4, 477–482. [Google Scholar] [CrossRef] [PubMed]
  34. Hartnett, L.; Egan, L.J. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 2012, 33, 723–731. [Google Scholar] [CrossRef] [PubMed]
  35. Collins, D.; Hogan, A.M.; Winter, D.C. Microbial and viral pathogens in colorectal cancer. Lancet Oncol. 2011, 12, 504–512. [Google Scholar] [CrossRef]
  36. Tjalsma, H.; Boleij, A.; Marchesi, J.R.; Dutilh, B.E. A bacterial driver-passenger model for colorectal cancer: Beyond the usual suspects. Nat. Rev. Microbiol. 2012, 10, 575–582. [Google Scholar] [CrossRef] [PubMed]
  37. Boleij, A.; van Gelder, M.M.; Swinkels, D.W.; Tjalsma, H. Clinical importance of streptococcus gallolyticus infection among colorectal cancer patients: Systematic review and meta-analysis. Clin. Infect. Dis. 2011, 53, 870–878. [Google Scholar] [CrossRef] [PubMed]
  38. Thomas, J.E.; Bassett, M.T.; Sigola, L.B.; Taylor, P. Relationship between bladder cancer incidence, Schistosoma haematobium infection, and geographical region in Zimbabwe. Trans. R. Soc. Trop. Med. Hyg. 1990, 84, 551–553. [Google Scholar] [CrossRef]
  39. West, D.A.; Cummings, J.M.; Longo, W.E.; Virgo, K.S.; Johnson, F.E.; Parra, R.O. Role of chronic catheterization in the development of bladder cancer in patients with spinal cord injury. Urology 1999, 53, 292–297. [Google Scholar] [CrossRef]
  40. Ky, A.; Sohn, N.; Weinstein, M.A.; Korelitz, B.I. Carcinoma arising in anorectal fistulas of Crohn’s disease. Dis. Colon Rectum. 1998, 41, 992–996. [Google Scholar] [CrossRef] [PubMed]
  41. Akre, O.; Lipworth, L.; Tretli, S.; Linde, A.; Engstrand, L.; Adami, H.O.; Melbye, M.; Andersen, A.; Ekbom, A. Epstein-Barr virus and cytomegalovirus in relation to testicular-cancer risk: A nested case-control study. Int. J. Cancer 1999, 82, 1–5. [Google Scholar] [CrossRef]
  42. De Marzo, A.M.; Platz, E.A.; Sutcliffe, S.; Xu, J.; Gronberg, H.; Drake, C.G.; Nakai, Y.; Isaacs, W.B.; Nelson, W.G. Inflammation in prostate carcinogenesis. Nat. Rev. Cancer 2007, 7, 256–269. [Google Scholar] [CrossRef] [PubMed]
  43. Dennis, L.K.; Dawson, D.V. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology 2002, 13, 72–79. [Google Scholar] [CrossRef] [PubMed]
  44. Stark, J.R.; Judson, G.; Alderete, J.F.; Mundodi, V.; Kucknoor, A.S.; Giovannucci, E.L.; Platz, E.A.; Sutcliffe, S.; Fall, K.; Kurth, T.; et al. Prospective study of Trichomonas vaginalis infection and prostate cancer incidence and mortality: Physicians’ health study. J. Natl. Cancer Inst. 2009, 101, 1406–1411. [Google Scholar] [CrossRef] [PubMed]
  45. Kralickova, M.; Vetvicka, V. Endometriosis and ovarian cancer. World J. Clin. Oncol. 2014, 5, 800–805. [Google Scholar] [CrossRef] [PubMed]
  46. Bleeker, M.C.; Visser, P.J.; Overbeek, L.I.; van Beurden, M.; Berkhof, J. Lichen sclerosus: Incidence and risk of vulvar squamous cell carcinoma. Cancer Epidemiol. Biomark. Prev. 2016, 25, 1224–1230. [Google Scholar] [CrossRef] [PubMed]
  47. Hejna, W.F. Squamous-cell carcinoma developing in the chronic draining sinuses of osteomyelitis. Cancer 1965, 18, 128–132. [Google Scholar] [CrossRef]
  48. Arron, S.T.; Jennings, L.; Nindl, I.; Rosl, F.; Bouwes Bavinck, J.N.; Seckin, D.; Trakatelli, M.; Murphy, G.M. Viral Working Group of the International Transplant Skin Cancer Collaborative (ITSCC); Care in Organ Transplant Patients, Europe (SCOPE). Viral oncogenesis and its role in nonmelanoma skin cancer. Br. J. Dermatol. 2011, 164, 1201–1213. [Google Scholar] [CrossRef] [PubMed]
  49. Reiss, K.; Khalili, K. Viruses and cancer: Lessons from the human polyomavirus, JCV. Oncogene 2003, 22, 6517–6523. [Google Scholar] [CrossRef] [PubMed]
  50. Dehio, C. Bartonella-host-cell interactions and vascular tumour formation. Nat. Rev. Microbiol. 2005, 3, 621–631. [Google Scholar] [CrossRef] [PubMed]
  51. Grulich, A.E.; van Leeuwen, M.T.; Falster, M.O.; Vajdic, C.M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet 2007, 370, 59–67. [Google Scholar] [CrossRef]
  52. Jeong, S.H. HBV infection as a risk factor for non-Hodgkin lymphoma. Lancet Oncol. 2010, 11, 806. [Google Scholar] [CrossRef]
  53. Colebunders, R.; de Vuyst, H.; Verstraeten, T.; Schroyens, W.; van Marck, E. A non-Hodgkin’s lymphoma in a patient with HIV-2 infection. Genitourin. Med. 1995, 71, 129. [Google Scholar] [CrossRef] [PubMed]
  54. Green, P.H.; Fleischauer, A.T.; Bhagat, G.; Goyal, R.; Jabri, B.; Neugut, A.I. Risk of malignancy in patients with celiac disease. Am. J. Med. 2003, 115, 191–195. [Google Scholar] [CrossRef]
  55. Galun, E.; Ilan, Y.; Livni, N.; Ketzinel, M.; Nahor, O.; Pizov, G.; Nagler, A.; Eid, A.; Rivkind, A.; Laster, M.; et al. Hepatitis B virus infection associated with hematopoietic tumors. Am. J. Pathol. 1994, 145, 1001–1007. [Google Scholar] [PubMed]
  56. Coffin, J.M. The discovery of HTLV-1, the first pathogenic human retrovirus. Proc. Natl. Acad. Sci. USA 2015, 112, 15525–15529. [Google Scholar] [CrossRef] [PubMed]
  57. Ferreri, A.J.; Guidoboni, M.; Ponzoni, M.; de Conciliis, C.; Dell’Oro, S.; Fleischhauer, K.; Caggiari, L.; Lettini, A.A.; Dal Cin, E.; Ieri, R.; et al. Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas. J. Natl. Cancer Inst. 2004, 96, 586–594. [Google Scholar] [CrossRef] [PubMed]
  58. Aozasa, K. Hashimoto’s thyroiditis as a risk factor of thyroid lymphoma. Acta Pathol. Jpn. 1990, 40, 459–468. [Google Scholar] [CrossRef] [PubMed]
  59. Molinie, V.; Pouchot, J.; Navratil, E.; Aubert, F.; Vinceneux, P.; Barge, J. Primary Epstein-Barr virus-related non-Hodgkin’s lymphoma of the pleural cavity following long-standing tuberculous empyema. Arch. Pathol. Lab. Med. 1996, 120, 288–291. [Google Scholar] [PubMed]
  60. Aozasa, K.; Takakuwa, T.; Nakatsuka, S. Pyothorax-associated lymphoma: A lymphoma developing in chronic inflammation. Adv. Anat. Pathol. 2005, 12, 324–331. [Google Scholar] [CrossRef] [PubMed]
  61. Lecuit, M.; Abachin, E.; Martin, A.; Poyart, C.; Pochart, P.; Suarez, F.; Bengoufa, D.; Feuillard, J.; Lavergne, A.; Gordon, J.I.; et al. Immunoproliferative small intestinal disease associated with Campylobacter jejuni. N. Engl. J. Med. 2004, 350, 239–248. [Google Scholar] [CrossRef] [PubMed]
  62. Goodlad, J.R.; Davidson, M.M.; Hollowood, K.; Ling, C.; MacKenzie, C.; Christie, I.; Batstone, P.J.; Ho-Yen, D.O. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the Highlands of Scotland. Am. J. Surg. Pathol. 2000, 24, 1279–1285. [Google Scholar] [CrossRef] [PubMed]
  63. Yasunaga, J.; Matsuoka, M. Molecular mechanisms of HTLV-1 infection and pathogenesis. Int. J. Hematol. 2011, 94, 435–442. [Google Scholar] [CrossRef] [PubMed]
  64. Piccaluga, P.P.; Gazzola, A.; Agostinelli, C.; Bacci, F.; Sabattini, E.; Pileri, S.A. Pathobiology of Epstein-Barr virus-driven peripheral T-cell lymphomas. Semin. Diagn. Pathol. 2011, 28, 234–244. [Google Scholar] [CrossRef] [PubMed]
  65. Rochford, R.; Moormann, A.M. Burkitt’s Lymphoma. Curr. Top. Microbiol. Immunol. 2015, 390, 267–285. [Google Scholar] [PubMed]
  66. Grywalska, E.; Rolinski, J. Epstein-Barr virus-associated lymphomas. Semin. Oncol. 2015, 42, 291–303. [Google Scholar] [CrossRef] [PubMed]
  67. Wen, K.W.; Damania, B. Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis. Cancer Lett. 2010, 289, 140–150. [Google Scholar] [CrossRef] [PubMed]
  68. Samaras, V.; Rafailidis, P.I.; Mourtzoukou, E.G.; Peppas, G.; Falagas, M.E. Chronic bacterial and parasitic infections and cancer: A review. J. Infect. Dev. Ctries 2010, 4, 267–281. [Google Scholar] [PubMed]
  69. Mesri, E.A.; Feitelson, M.A.; Munger, K. Human viral oncogenesis: A cancer hallmarks analysis. Cell Host Microbe 2014, 15, 266–282. [Google Scholar] [CrossRef] [PubMed]
  70. Wang, F.; Meng, W.; Wang, B.; Qiao, L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014, 345, 196–202. [Google Scholar] [CrossRef] [PubMed]
  71. Okada, F. Beyond foreign-body-induced carcinogenesis: Impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression. Int. J. Cancer 2007, 121, 2364–2372. [Google Scholar] [CrossRef] [PubMed]
  72. Nagai, H.; Toyokuni, S. Biopersistent fiber-induced inflammation and carcinogenesis: Lessons learned from asbestos toward safety of fibrous nanomaterials. Arch. Biochem. Biophys. 2010, 502, 1–7. [Google Scholar] [CrossRef] [PubMed]
  73. Chew, S.H.; Toyokuni, S. Malignant mesothelioma as an oxidative stress-induced cancer: An update. Free Radic. Biol. Med. 2015, 86, 166–178. [Google Scholar] [CrossRef] [PubMed]
  74. Kzhyshkowska, J.; Gudima, A.; Riabov, V.; Dollinger, C.; Lavalle, P.; Vrana, N.E. Macrophage responses to implants: Prospects for personalized medicine. J. Leukoc. Biol. 2015, 98, 953–962. [Google Scholar] [CrossRef] [PubMed]
  75. Nagai, H.; Toyokuni, S. Differences and similarities between carbon nanotubes and asbestos fibers during mesothelial carcinogenesis: Shedding light on fiber entry mechanism. Cancer Sci. 2012, 103, 1378–1390. [Google Scholar] [CrossRef] [PubMed]
  76. Xing, Y.F.; Xu, Y.H.; Shi, M.H.; Lian, Y.X. The impact of PM2.5 on the human respiratory system. J. Thorac. Dis. 2016, 8, E69–E74. [Google Scholar] [PubMed]
  77. Watanabe, M.; Noma, H.; Kurai, J.; Sano, H.; Saito, R.; Abe, S.; Kimura, Y.; Aiba, S.; Oshimura, M.; Yamasaki, A.; et al. Decreased pulmonary function in school children in Western Japan after exposures to Asian desert dusts and its association with interleukin-8. BioMed Res. Int. 2015, 2015, 583293. [Google Scholar] [CrossRef] [PubMed]
  78. Watanabe, M.; Noma, H.; Kurai, J.; Sano, H.; Kitano, H.; Saito, R.; Kimura, Y.; Aiba, S.; Oshimura, M.; Shimizu, E. Variation in the effect of particulate matter on pulmonary function in schoolchildren in western japan and its relation with interleukin-8. Int. J. Environ. Res. Public Health 2015, 12, 14229–14243. [Google Scholar] [CrossRef] [PubMed]
  79. Watanabe, M.; Noma, H.; Kurai, J.; Sano, H.; Ueda, Y.; Mikami, M.; Yamamoto, H.; Tokuyasu, H.; Kato, K.; Konishi, T.; et al. Differences in the effects of Asian dust on pulmonary function between adult patients with asthma and those with asthma-chronic obstructive pulmonary disease overlap syndrome. Int. J. Chronic Obstr. Pulm. Dis. 2016, 11, 183–190. [Google Scholar] [CrossRef] [PubMed]
  80. Turner, M.C.; Krewski, D.; Pope, C.A., III; Chen, Y.; Gapstur, S.M.; Thun, M.J. Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers. Am. J. Respir. Crit. Care Med. 2011, 184, 1374–1381. [Google Scholar] [CrossRef] [PubMed]
  81. King, P.T. Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer. Clin. Transl. Med. 2015, 4, 68. [Google Scholar] [CrossRef] [PubMed]
  82. Young, R.P.; Hopkins, R.J.; Christmas, T.; Black, P.N.; Metcalf, P.; Gamble, G.D. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur. Respir. J. 2009, 34, 380–386. [Google Scholar] [CrossRef] [PubMed]
  83. Hong, W.K.; Sporn, M.B. Recent advances in chemoprevention of cancer. Science 1997, 278, 1073–1077. [Google Scholar] [CrossRef] [PubMed]
  84. Miwa, K.; Sahara, H.; Segawa, M.; Kinami, S.; Sato, T.; Miyazaki, I.; Hattori, T. Reflux of duodenal or gastro-duodenal contents induces esophageal carcinoma in rats. Int. J. Cancer 1996, 67, 269–274. [Google Scholar] [CrossRef]
  85. Tatematsu, M.; Yamamoto, M.; Shimizu, N.; Yoshikawa, A.; Fukami, H.; Kaminishi, M.; Oohara, T.; Sugiyama, A.; Ikeno, T. Induction of glandular stomach cancers in Helicobacter pylori-sensitive Mongolian gerbils treated with N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine in drinking water. Jpn. J. Cancer Res. 1998, 89, 97–104. [Google Scholar] [CrossRef] [PubMed]
  86. Clapper, M.L.; Cooper, H.S.; Chang, W.C. Dextran sulfate sodium-induced colitis-associated neoplasia: A promising model for the development of chemopreventive interventions. Acta Pharmacol. Sin. 2007, 28, 1450–1459. [Google Scholar] [CrossRef] [PubMed]
  87. Tanaka, T. Animal models of carcinogenesis in inflamed colorectum: Potential use in chemoprevention study. Curr. Drug Targets 2012, 13, 1689–1697. [Google Scholar] [CrossRef] [PubMed]
  88. Dunsford, H.A.; Sell, S.; Chisari, F.V. Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res. 1990, 50, 3400–3407. [Google Scholar] [PubMed]
  89. Schiffer, E.; Housset, C.; Cacheux, W.; Wendum, D.; Desbois-Mouthon, C.; Rey, C.; Clergue, F.; Poupon, R.; Barbu, V.; Rosmorduc, O. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005, 41, 307–314. [Google Scholar] [CrossRef] [PubMed]
  90. Uehara, T.; Ainslie, G.R.; Kutanzi, K.; Pogribny, I.P.; Muskhelishvili, L.; Izawa, T.; Yamate, J.; Kosyk, O.; Shymonyak, S.; Bradford, B.U.; et al. Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis. Toxicol. Sci. 2013, 132, 53–63. [Google Scholar] [CrossRef] [PubMed]
  91. Thamavit, W.; Bhamarapravati, N.; Sahaphong, S.; Vajrasthira, S.; Angsubhakorn, S. Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters. Cancer Res. 1978, 38, 4634–4639. [Google Scholar] [PubMed]
  92. Tajima, Y.; Eto, T.; Tsunoda, T.; Tomioka, T.; Inoue, K.; Fukahori, T.; Kanematsu, T. Induction of extrahepatic biliary carcinoma by N-nitrosobis(2-oxopropyl)amine in hamsters given cholecystoduodenostomy with dissection of the common duct. Jpn. J. Cancer Res. 1994, 85, 780–788. [Google Scholar] [CrossRef] [PubMed]
  93. Guerra, C.; Schuhmacher, A.J.; Canamero, M.; Grippo, P.J.; Verdaguer, L.; Perez-Gallego, L.; Dubus, P.; Sandgren, E.P.; Barbacid, M. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 2007, 11, 291–302. [Google Scholar] [CrossRef] [PubMed]
  94. Schwarz, M.; Munzel, P.A.; Braeuning, A. Non-melanoma skin cancer in mouse and man. Arch. Toxicol. 2013, 87, 783–978. [Google Scholar] [CrossRef] [PubMed]
  95. Kapoor, H.; Lohani, K.R.; Lee, T.H.; Agrawal, D.K.; Mittal, S.K. Animal models of Barrett’s esophagus and esophageal adenocarcinoma—Past, present, and future. Clin. Transl. Sci. 2015, 8, 841–847. [Google Scholar] [CrossRef] [PubMed]
  96. Pham, T.H.; Genta, R.M.; Spechler, S.J.; Souza, R.F.; Wang, D.H. Development and characterization of a surgical mouse model of reflux esophagitis and Barrett’s esophagus. J. Gastrointest. Surg. 2014, 18, 234–240. [Google Scholar] [CrossRef] [PubMed]
  97. Buskens, C.J.; Hulscher, J.B.; van Gulik, T.M.; Ten Kate, F.J.; van Lanschot, J.J. Histopathologic evaluation of an animal model for Barrett’s esophagus and adenocarcinoma of the distal esophagus. J. Surg. Res. 2006, 135, 337–344. [Google Scholar] [CrossRef] [PubMed]
  98. Fox, J.G.; Wang, T.C.; Rogers, A.B.; Poutahidis, T.; Ge, Z.; Taylor, N.; Dangler, C.A.; Israel, D.A.; Krishna, U.; Gaus, K.; et al. Host and microbial constituents influence Helicobacter pylori-induced cancer in a murine model of hypergastrinemia. Gastroenterology 2003, 124, 1879–1890. [Google Scholar] [CrossRef]
  99. Rogers, A.B.; Fox, J.G. Inflammation and Cancer. I. Rodent models of infectious gastrointestinal and liver cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 2004, 286, G361–G366. [Google Scholar] [CrossRef] [PubMed]
  100. Tsukamoto, T.; Toyoda, T.; Mizoshita, T.; Tatematsu, M. Helicobacter pylori infection and gastric carcinogenesis in rodent models. Semin. Immunopathol. 2013, 35, 177–190. [Google Scholar] [CrossRef] [PubMed]
  101. Mohammadi, M.; Redline, R.; Nedrud, J.; Czinn, S. Role of the host in pathogenesis of Helicobacter-associated gastritis: H. felis infection of inbred and congenic mouse strains. Infect. Immun. 1996, 64, 238–245. [Google Scholar] [PubMed]
  102. Nakamura, Y.; Sakagami, T.; Yamamoto, N.; Yokota, Y.; Koizuka, H.; Hori, K.; Fukuda, Y.; Tanida, N.; Kobayashi, T.; Shimoyama, T. Helicobacter pylori does not promote N-methyl-N-nitrosourea-induced gastric carcinogenesis in SPF C57BL/6 mice. Jpn. J. Cancer Res. 2002, 93, 111–116. [Google Scholar] [CrossRef] [PubMed]
  103. Perse, M.; Cerar, A. Dextran sodium sulphate colitis mouse model: Traps and tricks. J. Biomed. Biotechnol. 2012, 2012, 718617. [Google Scholar] [CrossRef] [PubMed]
  104. Melgar, S.; Karlsson, A.; Michaelsson, E. Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: Correlation between symptoms and inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 288, 1328–1338. [Google Scholar] [CrossRef] [PubMed]
  105. Cooper, H.S.; Murthy, S.N.; Shah, R.S.; Sedergran, D.J. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Investig. 1993, 69, 238–249. [Google Scholar] [PubMed]
  106. Hursting, S.D.; Slaga, T.J.; Fischer, S.M.; DiGiovanni, J.; Phang, J.M. Mechanism-based cancer prevention approaches: Targets, examples, and the use of transgenic mice. J. Natl. Cancer Inst. 1999, 91, 215–225. [Google Scholar] [CrossRef] [PubMed]
  107. Kettunen, H.L.; Kettunen, A.S.; Rautonen, N.E. Intestinal immune responses in wild-type and Apcmin/+ mouse, a model for colon cancer. Cancer Res. 2003, 63, 5136–5142. [Google Scholar] [PubMed]
  108. Tanaka, T.; Kohno, H.; Suzuki, R.; Hata, K.; Sugie, S.; Niho, N.; Sakano, K.; Takahashi, M.; Wakabayashi, K. Dextran sodium sulfate strongly promotes colorectal carcinogenesis in ApcMin/+ mice: Inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int. J. Cancer 2006, 118, 25–34. [Google Scholar] [CrossRef] [PubMed]
  109. Bakiri, L.; Wagner, E.F. Mouse models for liver cancer. Mol. Oncol. 2013, 7, 206–223. [Google Scholar] [CrossRef] [PubMed]
  110. Babinet, C.; Farza, H.; Morello, D.; Hadchouel, M.; Pourcel, C. Specific expression of hepatitis B surface antigen (HBsAg) in transgenic mice. Science 1985, 230, 1160–1163. [Google Scholar] [CrossRef] [PubMed]
  111. McGivern, D.R.; Lemon, S.M. Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer. Oncogene 2011, 30, 1969–1983. [Google Scholar] [CrossRef] [PubMed]
  112. Rajewsky, M.F.; Dauber, W.; Frankenberg, H. Liver carcinogenesis by diethylnitrosamine in the rat. Science 1966, 152, 83–85. [Google Scholar] [CrossRef] [PubMed]
  113. Thamavit, W.; Kongkanuntn, R.; Tiwawech, D.; Moore, M.A. Level of Opisthorchis infestation and carcinogen dose-dependence of cholangiocarcinoma induction in Syrian golden hamsters. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol. 1987, 54, 52–58. [Google Scholar] [CrossRef] [PubMed]
  114. Parkin, D.M.; Ohshima, H.; Srivatanakul, P.; Vatanasapt, V. Cholangiocarcinoma: Epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol. Biomark. Prev. 1993, 2, 537–544. [Google Scholar]
  115. Ames, B.N.; Gold, L.S. Chemical carcinogenesis: Too many rodent carcinogens. Proc. Natl. Acad. Sci. USA 1990, 87, 7772–7776. [Google Scholar] [CrossRef] [PubMed]
  116. Cohen, S.M.; Ellwein, L.B. Cell proliferation in carcinogenesis. Science 1990, 249, 1007–1011. [Google Scholar] [CrossRef] [PubMed]
  117. Weitzman, S.A.; Gordon, L.I. Inflammation and cancer: Role of phagocyte-generated oxidants in carcinogenesis. Blood 1990, 76, 655–663. [Google Scholar] [PubMed]
  118. Li, X.; Wang, S.; Zhu, R.; Li, H.; Han, Q.; Zhao, R.C. Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NF-κB-TLR signaling pathway. J. Hematol. Oncol. 2016, 9, 42. [Google Scholar] [CrossRef] [PubMed]
  119. Chaiyadet, S.; Sotillo, J.; Smout, M.; Cantacessi, C.; Jones, M.K.; Johnson, M.S.; Turnbull, L.; Whitchurch, C.B.; Potriquet, J.; Laohaviroj, M.; et al. Carcinogenic liver fluke secretes extracellular vesicles that promote cholangiocytes to adopt a tumorigenic phenotype. J. Infect. Dis. 2015, 212, 1636–1645. [Google Scholar] [CrossRef] [PubMed]
  120. Tsuchida, A.; Itoi, T. Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction. World J. Gastrointest. Oncol. 2010, 2, 130–135. [Google Scholar] [CrossRef] [PubMed]
  121. Tajima, Y.; Kitajima, T.; Tomioka, T.; Eto, T.; Inoue, K.; Fukahori, T.; Sasaki, M.; Tsunoda, T. Hamster Models of Biliary Carcinoma. In Hepatobiliary and Pancreatic Carcinogenesis in the Hamster; Springer: Heidelberg, Germany; Dordrecht, The Netherlands, 2009; pp. 29–68. [Google Scholar]
  122. Tsuchida, A.; Itoi, T.; Kasuya, K.; Endo, M.; Katsumata, K.; Aoki, T.; Suzuki, M.; Aoki, T. Inhibitory effect of meloxicam, a cyclooxygenase-2 inhibitor, on N-nitrosobis (2-oxopropyl) amine induced biliary carcinogenesis in Syrian hamsters. Carcinogenesis 2005, 26, 1922–1928. [Google Scholar] [CrossRef] [PubMed]
  123. Bos, J.L. ras Oncogenes in human cancer: A review. Cancer Res. 1989, 49, 4682–4689. [Google Scholar] [PubMed]
  124. Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988, 53, 549–554. [Google Scholar] [CrossRef]
  125. Boone, C.W.; Steele, V.E.; Kelloff, G.J. Screening for chemopreventive (anticarcinogenic) compounds in rodents. Mutat. Res. 1992, 267, 251–255. [Google Scholar] [CrossRef]
  126. Hennings, H.; Glick, A.B.; Lowry, D.T.; Krsmanovic, L.S.; Sly, L.M.; Yuspa, S.H. FVB/N mice: An inbred strain sensitive to the chemical induction of squamous cell carcinomas in the skin. Carcinogenesis 1993, 14, 2353–2358. [Google Scholar] [CrossRef] [PubMed]
  127. Nassar, D.; Latil, M.; Boeckx, B.; Lambrechts, D.; Blanpain, C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat. Med. 2015, 21, 946–954. [Google Scholar] [CrossRef] [PubMed]
  128. Tazawa, H.; Tatemichi, M.; Sawa, T.; Gilibert, I.; Ma, N.; Hiraku, Y.; Donehower, L.A.; Ohgaki, H.; Kawanishi, S.; Ohshima, H. Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/− mice. Carcinogenesis 2007, 28, 191–198. [Google Scholar] [CrossRef] [PubMed]
  129. Jennings, T.A.; Peterson, L.; Axiotis, C.A.; Friedlaender, G.E.; Cooke, R.A.; Rosai, J. Angiosarcoma associated with foreign body material. A report of three cases. Cancer 1988, 62, 2436–2444. [Google Scholar] [CrossRef]
  130. Okada, F.; Kawaguchi, T.; Habelhah, H.; Kobayashi, T.; Tazawa, H.; Takeichi, N.; Kitagawa, T.; Hosokawa, M. Conversion of human colonic adenoma cells to adenocarcinoma cells through inflammation in nude mice. Lab. Investig. 2000, 80, 1617–1628. [Google Scholar] [CrossRef] [PubMed]
  131. Tazawa, H.; Kawaguchi, T.; Kobayashi, T.; Kuramitsu, Y.; Wada, S.; Satomi, Y.; Nishino, H.; Kobayashi, M.; Kanda, Y.; Osaki, M.; et al. Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells. Exp. Cell Res. 2013, 319, 2835–2844. [Google Scholar] [CrossRef] [PubMed]
  132. Kanda, Y.; Kawaguchi, T.; Kuramitsu, Y.; Kitagawa, T.; Kobayashi, T.; Takahashi, N.; Tazawa, H.; Habelhah, H.; Hamada, J.; Kobayashi, M.; et al. Fascin regulates chronic inflammation-related human colon carcinogenesis by inhibiting cell anoikis. Proteomics 2014, 14, 1031–1041. [Google Scholar] [CrossRef] [PubMed]
  133. Okada, F.; Hosokawa, M.; Hamada, J.I.; Hasegawa, J.; Kato, M.; Mizutani, M.; Ren, J.; Takeichi, N.; Kobayashi, H. Malignant progression of a mouse fibrosarcoma by host cells reactive to a foreign body (gelatin sponge). Br. J. Cancer 1992, 66, 635–639. [Google Scholar] [CrossRef] [PubMed]
  134. Tazawa, H.; Okada, F.; Kobayashi, T.; Tada, M.; Mori, Y.; Une, Y.; Sendo, F.; Kobayashi, M.; Hosokawa, M. Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: Implication of inflammation-associated carcinogenesis and tumor progression. Am. J. Pathol. 2003, 163, 2221–2232. [Google Scholar] [CrossRef]
  135. Okada, F. Inflammation-related carcinogenesis: Current findings in epidemiological trends, causes and mechanisms. Yonago Acta Med. 2014, 57, 65–72. [Google Scholar] [PubMed]
  136. Hamilton, J.A.; Achuthan, A. Colony stimulating factors and myeloid cell biology in health and disease. Trends Immunol. 2013, 34, 81–89. [Google Scholar] [CrossRef] [PubMed]
  137. Yang, L.; Zhang, Y. Tumor-associated macrophages: From basic research to clinical application. J. Hematol. Oncol. 2017, 10, 58. [Google Scholar] [CrossRef] [PubMed]
  138. Morales, C.; Rachidi, S.; Hong, F.; Sun, S.; Ouyang, X.; Wallace, C.; Zhang, Y.; Garret-Mayer, E.; Wu, J.; Liu, B.; et al. Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res. 2014, 74, 446–459. [Google Scholar] [CrossRef] [PubMed]
  139. Zhao, H.; Zhang, X.; Chen, X.; Li, Y.; Ke, Z.; Tang, T.; Chai, H.; Guo, A.M.; Chen, H.; Yang, J. Isoliquiritigenin, a flavonoid from licorice, blocks M2 macrophage polarization in colitis-associated tumorigenesis through downregulating PGE2 and IL-6. Toxicol. Appl. Pharmacol. 2014, 279, 311–321. [Google Scholar] [CrossRef] [PubMed]
  140. Roncucci, L.; Mora, E.; Mariani, F.; Bursi, S.; Pezzi, A.; Rossi, G.; Pedroni, M.; Luppi, D.; Santoro, L.; Monni, S.; et al. Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk. Cancer Epidemiol. Biomark. Prev. 2008, 17, 2291–2297. [Google Scholar] [CrossRef] [PubMed]
  141. Coussens, L.M.; Werb, Z. Inflammation and cancer. Nature 2002, 420, 860–867. [Google Scholar] [CrossRef] [PubMed]
  142. Popivanova, B.K.; Kostadinova, F.I.; Furuichi, K.; Shamekh, M.M.; Kondo, T.; Wada, T.; Egashira, K.; Mukaida, N. Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. Cancer Res. 2009, 69, 7884–7892. [Google Scholar] [CrossRef] [PubMed]
  143. Horemans, T.; Boulet, G.; van Kerckhoven, M.; Bogers, J.; Thys, S.; Vervaet, C.; Vervaeck, A.; Delputte, P.; Maes, L.; Cos, P. In Vivo evaluation of apocynin for prevention of Helicobacter pylori-induced gastric carcinogenesis. Eur. J. Cancer Prev. 2017, 26, 10–16. [Google Scholar] [CrossRef] [PubMed]
  144. Liu, L.; Li, Y.H.; Niu, Y.B.; Sun, Y.; Guo, Z.J.; Li, Q.; Li, C.; Feng, J.; Cao, S.S.; Mei, Q.B. An apple oligogalactan prevents against inflammation and carcinogenesis by targeting LPS/TLR4/NF-κB pathway in a mouse model of colitis-associated colon cancer. Carcinogenesis 2010, 31, 1822–1832. [Google Scholar] [CrossRef] [PubMed]
  145. Onuma, K.; Kanda, Y.; Suzuki Ikeda, S.; Sakaki, R.; Nonomura, T.; Kobayashi, M.; Osaki, M.; Shikanai, M.; Kobayashi, H.; Okada, F. Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) prevents inflammation-related carcinogenesis in mice, through inhibition of inflammatory cell infiltration. Nutrients 2015, 7, 10237–10250. [Google Scholar] [CrossRef] [PubMed]
  146. Sliva, D.; Loganathan, J.; Jiang, J.; Jedinak, A.; Lamb, J.G.; Terry, C.; Baldridge, L.A.; Adamec, J.; Sandusky, G.E.; Dudhgaonkar, S. Mushroom Ganoderma lucidum prevents colitis-associated carcinogenesis in mice. PLoS ONE 2012, 7, e47873. [Google Scholar] [CrossRef] [PubMed]
  147. Lin, J.A.; Chen, H.C.; Yen, G.C. The preventive role of breadfruit against inflammation-associated epithelial carcinogenesis in mice. Mol. Nutr. Food Res. 2014, 58, 206–210. [Google Scholar] [CrossRef] [PubMed]
  148. Im, S.A.; Kim, J.W.; Kim, H.S.; Park, C.S.; Shin, E.; Do, S.G.; Park, Y.I.; Lee, C.K. Prevention of azoxymethane/dextran sodium sulfate-induced mouse colon carcinogenesis by processed Aloe vera gel. Int. Immunopharmacol. 2016, 40, 428–435. [Google Scholar] [CrossRef] [PubMed]
  149. Ju, J.; Hao, X.; Lee, M.J.; Lambert, J.D.; Lu, G.; Xiao, H.; Newmark, H.L.; Yang, C.S. A γ-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice. Cancer Prev. Res. 2009, 2, 143–152. [Google Scholar] [CrossRef] [PubMed]
  150. Onuma, K.; Suenaga, Y.; Sakaki, R.; Yoshitome, S.; Sato, Y.; Ogawara, S.; Suzuki, S.; Kuramitsu, Y.; Yokoyama, H.; Murakami, A.; et al. Development of a quantitative bioassay to assess preventive compounds against inflammation-based carcinogenesis. Nitric Oxide 2011, 25, 183–194. [Google Scholar] [CrossRef] [PubMed]
  151. Cao, X.; Tsukamoto, T.; Seki, T.; Tanaka, H.; Morimura, S.; Cao, L.; Mizoshita, T.; Ban, H.; Toyoda, T.; Maeda, H.; et al. 4-Vinyl-2,6-dimethoxyphenol (canolol) suppresses oxidative stress and gastric carcinogenesis in Helicobacter pylori-infected carcinogen-treated Mongolian gerbils. Int. J. Cancer 2008, 122, 1445–1454. [Google Scholar] [CrossRef] [PubMed]
  152. Du, Q.; Wang, Y.; Liu, C.; Wang, H.; Fan, H.; Li, Y.; Wang, J.; Zhang, X.; Lu, J.; Ji, H.; et al. Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2-β-catenin axis. Oncotarget 2016, 7, 17870–17884. [Google Scholar] [CrossRef] [PubMed]
  153. Chaudhary, S.C.; Siddiqui, M.S.; Athar, M.; Alam, M.S. Geraniol inhibits murine skin tumorigenesis by modulating COX-2 expression, Ras-ERK1/2 signaling pathway and apoptosis. J. Appl. Toxicol. 2013, 33, 828–837. [Google Scholar] [CrossRef] [PubMed]
  154. Kuo, Y.C.; Lai, C.S.; Tsai, C.Y.; Nagabhushanam, K.; Ho, C.T.; Pan, M.H. Inotilone suppresses phorbol ester-induced inflammation and tumor promotion in mouse skin. Mol. Nutr. Food Res. 2012, 56, 1324–1332. [Google Scholar] [CrossRef] [PubMed]
  155. Viennois, E.; Xiao, B.; Ayyadurai, S.; Wang, L.; Wang, P.G.; Zhang, Q.; Chen, Y.; Merlin, D. Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer. Lab. Investig. 2014, 94, 950–965. [Google Scholar] [CrossRef] [PubMed]
  156. Murakami, A.; Nakamura, Y.; Torikai, K.; Tanaka, T.; Koshiba, T.; Koshimizu, K.; Kuwahara, S.; Takahashi, Y.; Ogawa, K.; Yano, M.; et al. Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res. 2000, 60, 5059–5066. [Google Scholar] [PubMed]
  157. Meeker, S.; Seamons, A.; Paik, J.; Treuting, P.M.; Brabb, T.; Grady, W.M.; Maggio-Price, L. Increased dietary vitamin D suppresses MAPK signaling, colitis, and colon cancer. Cancer Res. 2014, 74, 4398–4408. [Google Scholar] [CrossRef] [PubMed]
  158. Liao, J.; Seril, D.N.; Yang, A.L.; Lu, G.G.; Yang, G.Y. Inhibition of chronic ulcerative colitis associated adenocarcinoma development in mice by inositol compounds. Carcinogenesis 2007, 28, 446–454. [Google Scholar] [CrossRef] [PubMed]
  159. Wei, T.T.; Lin, Y.T.; Tseng, R.Y.; Shun, C.T.; Lin, Y.C.; Wu, M.S.; Fang, J.M.; Chen, C.C. Prevention of colitis and colitis-associated colorectal cancer by a novel polypharmacological histone deacetylase inhibitor. Clin Cancer Res. 2016, 22, 4158–4169. [Google Scholar] [CrossRef] [PubMed]
  160. Trivedi, P.P.; Jena, G.B.; Tikoo, K.B.; Kumar, V. Melatonin modulated autophagy and Nrf2 signaling pathways in mice with colitis-associated colon carcinogenesis. Mol. Carcinog. 2016, 55, 255–267. [Google Scholar] [CrossRef] [PubMed]
  161. Chen, X.; Li, N.; Wang, S.; Hong, J.; Fang, M.; Yousselfson, J.; Yang, P.; Newman, R.A.; Lubet, R.A.; Yang, C.S. Aberrant arachidonic acid metabolism in esophageal adenocarcinogenesis, and the effects of sulindac, nordihydroguaiaretic acid, and α-difluoromethylornithine on tumorigenesis in a rat surgical model. Carcinogenesis 2002, 23, 2095–2102. [Google Scholar] [CrossRef] [PubMed]
  162. Doulberis, M.; Angelopoulou, K.; Kaldrymidou, E.; Tsingotjidou, A.; Abas, Z.; Erdman, S.E.; Poutahidis, T. Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer. Carcinogenesis 2015, 36, 280–290. [Google Scholar] [CrossRef] [PubMed]
  163. Ikeuchi, H.; Kinjo, T.; Klinman, D.M. Effect of suppressive oligodeoxynucleotides on the development of inflammation-induced papillomas. Cancer Prev. Res. 2011, 4, 752–757. [Google Scholar] [CrossRef] [PubMed]
  164. Yasuda, M.; Nishizawa, T.; Ohigashi, H.; Tanaka, T.; Hou, D.X.; Colburn, N.H.; Murakami, A. Linoleic acid metabolite suppresses skin inflammation and tumor promotion in mice: Possible roles of programmed cell death 4 induction. Carcinogenesis 2009, 30, 1209–1216. [Google Scholar] [CrossRef] [PubMed]
  165. Ohnishi, Y.; Fujii, H.; Kimura, F.; Mishima, T.; Murata, J.; Tazawa, K.; Fujimaki, M.; Okada, F.; Hosokawa, M.; Saiki, I. Inhibitory effect of a traditional Chinese medicine, Juzen-taiho-to, on progressive growth of weakly malignant clone cells derived from murine fibrosarcoma. Jpn. J. Cancer Res. 1996, 87, 1039–1044. [Google Scholar] [CrossRef] [PubMed]
  166. Yum, H.W.; Zhong, X.; Park, J.; Na, H.K.; Kim, N.; Lee, H.S.; Surh, Y.J. Oligonol inhibits dextran sulfate sodium-induced colitis and colonic adenoma formation in mice. Antioxid. Redox Signal. 2013, 19, 102–114. [Google Scholar] [CrossRef] [PubMed]
  167. Liu, J.; Gu, X.; Robbins, D.; Li, G.; Shi, R.; McCord, J.M.; Zhao, Y. Protandim, a fundamentally new antioxidant approach in chemoprevention using mouse two-stage skin carcinogenesis as a model. PLoS ONE 2009, 4, e5284. [Google Scholar] [CrossRef] [PubMed]
  168. Miyoshi, N.; Takabayashi, S.; Osawa, T.; Nakamura, Y. Benzyl isothiocyanate inhibits excessive superoxide generation in inflammatory leukocytes: Implication for prevention against inflammation-related carcinogenesis. Carcinogenesis 2004, 25, 567–575. [Google Scholar] [CrossRef] [PubMed]
  169. Ma, J.Y.; Li, R.H.; Huang, K.; Tan, G.; Li, C.; Zhi, F.C. Increased expression and possible role of chitinase 3-like-1 in a colitis-associated carcinoma model. World J. Gastroenterol. 2014, 20, 15736–15744. [Google Scholar] [CrossRef] [PubMed]
  170. Kawabata, K.; Tung, N.H.; Shoyama, Y.; Sugie, S.; Mori, T.; Tanaka, T. Dietary crocin inhibits colitis and colitis-associated colorectal carcinogenesis in male ICR mice. Evid. Based Complement. Altern. Med. eCAM 2012, 2012, 820415. [Google Scholar] [CrossRef] [PubMed]
  171. Cheung, K.L.; Khor, T.O.; Huang, M.T.; Kong, A.N. Differential in vivo mechanism of chemoprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM. Carcinogenesis 2010, 31, 880–885. [Google Scholar] [CrossRef] [PubMed]
  172. Yang, Y.; Cai, X.; Yang, J.; Sun, X.; Hu, C.; Yan, Z.; Xu, X.; Lu, W.; Wang, X.; Cao, P. Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation. Mol. Cancer 2014, 13, 48. [Google Scholar] [CrossRef] [PubMed]
  173. Tanaka, T.; de Azevedo, M.B.; Duran, N.; Alderete, J.B.; Epifano, F.; Genovese, S.; Tanaka, M.; Tanaka, T.; Curini, M. Colorectal cancer chemoprevention by 2β-cyclodextrin inclusion compounds of auraptene and 4’-geranyloxyferulic acid. Int. J. Cancer 2010, 126, 830–840. [Google Scholar] [CrossRef] [PubMed]
  174. Liu, Z.; Shen, C.; Tao, Y.; Wang, S.; Wei, Z.; Cao, Y.; Wu, H.; Fan, F.; Lin, C.; Shan, Y.; et al. Chemopreventive efficacy of menthol on carcinogen-induced cutaneous carcinoma through inhibition of inflammation and oxidative stress in mice. Food Chem. Toxicol. 2015, 82, 12–18. [Google Scholar] [CrossRef] [PubMed]
  175. Kuno, T.; Hatano, Y.; Tomita, H.; Hara, A.; Hirose, Y.; Hirata, A.; Mori, H.; Terasaki, M.; Masuda, S.; Tanaka, T. Organomagnesium suppresses inflammation-associated colon carcinogenesis in male Crj: CD-1 mice. Carcinogenesis 2013, 34, 361–369. [Google Scholar] [CrossRef] [PubMed]
  176. Okada, F.; Shionoya, H.; Kobayashi, M.; Kobayashi, T.; Tazawa, H.; Onuma, K.; Iuchi, Y.; Matsubara, N.; Ijichi, T.; Dugas, B.; 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, 854–862. [Google Scholar] [CrossRef] [PubMed]
  177. Habelhah, H.; Okada, F.; Nakai, K.; Choi, S.K.; Hamada, J.; Kobayashi, M.; Hosokawa, M. Polysaccharide K induces Mn superoxide dismutase (Mn-SOD) in tumor tissues and inhibits malignant progression of QR-32 tumor cells: Possible roles of interferon α, tumor necrosis factor α and transforming growth factor β in Mn-SOD induction by polysaccharide K. Cancer Immunol. Immunother. 1998, 46, 338–344. [Google Scholar] [PubMed]
  178. Khan, A.Q.; Khan, R.; Tahir, M.; Rehman, M.U.; Lateef, A.; Ali, F.; Hamiza, O.O.; Hasan, S.K.; Sultana, S. Silibinin inhibits tumor promotional triggers and tumorigenesis against chemically induced two-stage skin carcinogenesis in Swiss albino mice: Possible role of oxidative stress and inflammation. Nutr. Cancer 2014, 66, 249–258. [Google Scholar] [CrossRef] [PubMed]
  179. Jiang, Q.; Jiang, Z.; Hall, Y.J.; Jang, Y.; Snyder, P.W.; Bain, C.; Huang, J.; Jannasch, A.; Cooper, B.; Wang, Y.; et al. γ-Tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice. Free Radic. Biol. Med. 2013, 65, 1069–1077. [Google Scholar] [CrossRef] [PubMed]
  180. Kim, Y.H.; Kwon, H.S.; Kim, D.H.; Shin, E.K.; Kang, Y.H.; Park, J.H.; Shin, H.K.; Kim, J.K. 3,3′-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice. Inflamm. Bowel Dis. 2009, 15, 1164–1173. [Google Scholar] [CrossRef] [PubMed]
  181. Xi, M.Y.; Jia, J.M.; Sun, H.P.; Sun, Z.Y.; Jiang, J.W.; Wang, Y.J.; Zhang, M.Y.; Zhu, J.F.; Xu, L.L.; Jiang, Z.Y.; et al. 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones as potent Nrf2/ARE inducers in human cancer cells and AOM-DSS treated mice. J. Med. Chem. 2013, 56, 7925–7938. [Google Scholar] [CrossRef] [PubMed]
  182. Hamada, J.; Nakata, D.; Nakae, D.; Kobayashi, Y.; Akai, H.; Konishi, Y.; Okada, F.; Shibata, T.; Hosokawa, M.; Moriuchi, T. Increased oxidative DNA damage in mammary tumor cells by continuous epidermal growth factor stimulation. J. Natl. Cancer Inst. 2001, 93, 214–219. [Google Scholar] [CrossRef] [PubMed]
  183. Sanchez-Fidalgo, S.; Villegas, I.; Cardeno, A.; Talero, E.; Sanchez-Hidalgo, M.; Motilva, V.; Alarcon de la Lastra, C. Extra-virgin olive oil-enriched diet modulates DSS-colitis-associated colon carcinogenesis in mice. Clin. Nutr. 2010, 29, 663–673. [Google Scholar] [CrossRef] [PubMed]
  184. Phutthaphadoong, S.; Yamada, Y.; Hirata, A.; Tomita, H.; Hara, A.; Limtrakul, P.; Iwasaki, T.; Kobayashi, H.; Mori, H. Chemopreventive effect of fermented brown rice and rice bran (FBRA) on the inflammation-related colorectal carcinogenesis in ApcMin/+ mice. Oncol. Rep. 2010, 23, 53–59. [Google Scholar] [PubMed]
  185. Yasui, Y.; Hosokawa, M.; Mikami, N.; Miyashita, K.; Tanaka, T. Dietary astaxanthin inhibits colitis and colitis-associated colon carcinogenesis in mice via modulation of the inflammatory cytokines. Chem. Biol. Interact. 2011, 193, 79–87. [Google Scholar] [CrossRef] [PubMed]
  186. Ma, G.Z.; Liu, C.H.; Wei, B.; Qiao, J.; Lu, T.; Wei, H.C.; Chen, H.D.; He, C.D. Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation. Inflammation 2013, 36, 457–467. [Google Scholar] [CrossRef] [PubMed]
  187. Kim, D.H.; Sung, B.; Kang, Y.J.; Jang, J.Y.; Hwang, S.Y.; Lee, Y.; Kim, M.; Im, E.; Yoon, J.H.; Kim, C.M.; et al. Anti-inflammatory effects of betaine on AOM/DSS induced colon tumorigenesis in ICR male mice. Int. J. Oncol. 2014, 45, 1250–1256. [Google Scholar] [CrossRef] [PubMed]
  188. Prakobwong, S.; Khoontawad, J.; Yongvanit, P.; Pairojkul, C.; Hiraku, Y.; Sithithaworn, P.; Pinlaor, P.; Aggarwal, B.B.; Pinlaor, S. Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis. Int. J. Cancer 2011, 129, 88–100. [Google Scholar] [CrossRef] [PubMed]
  189. Tsai, M.L.; Lai, C.S.; Chang, Y.H.; Chen, W.J.; Ho, C.T.; Pan, M.H. Pterostilbene, a natural analogue of resveratrol, potently inhibits 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis. Food Funct. 2012, 3, 1185–1194. [Google Scholar] [CrossRef] [PubMed]
  190. Kohno, H.; Suzuki, R.; Yasui, Y.; Miyamoto, S.; Wakabayashi, K.; Tanaka, T. Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice. Clin. Cancer Res. 2007, 13, 2519–2525. [Google Scholar] [CrossRef] [PubMed]
  191. Lai, C.S.; Li, S.; Chai, C.Y.; Lo, C.Y.; Ho, C.T.; Wang, Y.J.; Pan, M.H. Inhibitory effect of citrus 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumor promotion in mice. Carcinogenesis 2007, 28, 2581–2588. [Google Scholar] [CrossRef] [PubMed]
  192. Kohno, H.; Suzuki, R.; Sugie, S.; Tanaka, T. Suppression of colitis-related mouse colon carcinogenesis by a COX-2 inhibitor and PPAR ligands. BMC Cancer 2005, 5, 46. [Google Scholar] [CrossRef] [PubMed]
  193. Shimizu, M.; Kochi, T.; Shirakami, Y.; Genovese, S.; Epifano, F.; Fiorito, S.; Mori, T.; Tanaka, T.; Moriwaki, H. A newly synthesized compound, 4′-geranyloxyferulic acid-N(omega)-nitro-l-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice. Int. J. Cancer 2014, 135, 774–784. [Google Scholar] [CrossRef] [PubMed]
  194. Kim, Y.J.; Lee, J.S.; Hong, K.S.; Chung, J.W.; Kim, J.H.; Hahm, K.B. Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression. Cancer Prev. Res. 2010, 3, 963–974. [Google Scholar] [CrossRef] [PubMed]
  195. Mishima, T.; Tajima, Y.; Kuroki, T.; Kosaka, T.; Adachi, T.; Kitasato, A.; Tsuneoka, N.; Kitajima, T.; Kanematsu, T. Chemopreventative effect of an inducible nitric oxide synthase inhibitor, ONO-1714, on inflammation-associated biliary carcinogenesis in hamsters. Carcinogenesis 2009, 30, 1763–1767. [Google Scholar] [CrossRef] [PubMed]
  196. Guo, Y.; Liu, Y.; Zhang, C.; Su, Z.Y.; Li, W.; Huang, M.T.; Kong, A.N. The epigenetic effects of aspirin: The modification of histone H3 lysine 27 acetylation in the prevention of colon carcinogenesis in azoxymethane- and dextran sulfate sodium-treated CF-1 mice. Carcinogenesis 2016, 37, 616–624. [Google Scholar] [CrossRef] [PubMed]
  197. Tian, Y.; Wang, K.; Wang, Z.; Li, N.; Ji, G. Chemopreventive effect of dietary glutamine on colitis-associated colon tumorigenesis in mice. Carcinogenesis 2013, 34, 1593–1600. [Google Scholar] [CrossRef] [PubMed]
  198. Chung, K.S.; Choi, H.E.; Shin, J.S.; Cho, E.J.; Cho, Y.W.; Choi, J.H.; Baek, N.I.; Lee, K.T. Chemopreventive effects of standardized ethanol extract from the aerial parts of Artemisia princeps Pampanini cv. Sajabal via NF-κB inactivation on colitis-associated colon tumorigenesis in mice. Food Chem. Toxicol. 2015, 75, 14–23. [Google Scholar] [CrossRef] [PubMed]
  199. Lavi, I.; Nimri, L.; Levinson, D.; Peri, I.; Hadar, Y.; Schwartz, B. Glucans from the edible mushroom Pleurotus pulmonarius inhibit colitis-associated colon carcinogenesis in mice. J. Gastroenterol. 2012, 47, 504–518. [Google Scholar] [CrossRef] [PubMed]
  200. Oyama, T.; Yasui, Y.; Sugie, S.; Koketsu, M.; Watanabe, K.; Tanaka, T. Dietary tricin suppresses inflammation-related colon carcinogenesis in male Crj: CD-1 mice. Cancer Prev. Res. 2009, 2, 1031–1038. [Google Scholar] [CrossRef] [PubMed]
  201. Kangwan, N.; Kim, Y.J.; Han, Y.M.; Jeong, M.; Park, J.M.; Go, E.J.; Hahm, K.B. Sonic hedgehog inhibitors prevent colitis-associated cancer via orchestrated mechanisms of IL-6/gp130 inhibition, 15-PGDH induction, Bcl-2 abrogation, and tumorsphere inhibition. Oncotarget 2016, 7, 7667–7682. [Google Scholar] [PubMed]
  202. Polytarchou, C.; Hommes, D.W.; Palumbo, T.; Hatziapostolou, M.; Koutsioumpa, M.; Koukos, G.; van der Meulen-de Jong, A.E.; Oikonomopoulos, A.; van Deen, W.K.; Vorvis, C.; et al. MicroRNA214 is associated with progression of ulcerative colitis, and inhibition reduces development of colitis and colitis-associated cancer in mice. Gastroenterology 2015, 149, 981–992. [Google Scholar] [CrossRef] [PubMed]
  203. Yang, X.; Zhang, F.; Wang, Y.; Cai, M.; Wang, Q.; Guo, Q.; Li, Z.; Hu, R. Oroxylin A inhibits colitis-associated carcinogenesis through modulating the IL-6/STAT3 signaling pathway. Inflamm. Bowel Dis. 2013, 19, 1990–2000. [Google Scholar] [CrossRef] [PubMed]
  204. Wang, Z.; Jin, H.; Xu, R.; Mei, Q.; Fan, D. Triptolide downregulates Rac1 and the JAK/STAT3 pathway and inhibits colitis-related colon cancer progression. Exp. Mol. Med. 2009, 41, 717–727. [Google Scholar] [CrossRef] [PubMed]
  205. Altamemi, I.; Murphy, E.A.; Catroppo, J.F.; Zumbrun, E.E.; Zhang, J.; McClellan, J.L.; Singh, U.P.; Nagarkatti, P.S.; Nagarkatti, M. Role of microRNAs in resveratrol-mediated mitigation of colitis-associated tumorigenesis in ApcMin/+ mice. J. Pharmacol. Exp. Ther. 2014, 350, 99–109. [Google Scholar] [CrossRef] [PubMed]
  206. Zhang, L.; Han, J.; Jackson, A.L.; Clark, L.N.; Kilgore, J.; Guo, H.; Livingston, N.; Batchelor, K.; Yin, Y.; Gilliam, T.P.; et al. NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo. J. Hematol. Oncol. 2016, 9, 91. [Google Scholar] [CrossRef] [PubMed]
  207. Niwa, T.; Toyoda, T.; Tsukamoto, T.; Mori, A.; Tatematsu, M.; Ushijima, T. Prevention of Helicobacter pylori-induced gastric cancers in gerbils by a DNA demethylating agent. Cancer Prev. Res. 2013, 6, 263–270. [Google Scholar] [CrossRef] [PubMed]
  208. Yamaguchi, M.; Takai, S.; Hosono, A.; Seki, T. Bovine milk-derived α-lactalbumin inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sodium sulfate-treated mice. Biosci. Biotechnol. Biochem. 2014, 78, 672–679. [Google Scholar] [CrossRef] [PubMed]
  209. Piazzi, G.; D’Argenio, G.; Prossomariti, A.; Lembo, V.; Mazzone, G.; Candela, M.; Biagi, E.; Brigidi, P.; Vitaglione, P.; Fogliano, V.; et al. Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota. Int. J. Cancer 2014, 135, 2004–2013. [Google Scholar] [CrossRef] [PubMed]
  210. Kuo, C.H.; Hu, H.M.; Tsai, P.Y.; Wu, I.C.; Yang, S.F.; Chang, L.L.; Wang, J.Y.; Jan, C.M.; Wang, W.M.; Wu, D.C. Short-term celecoxib intervention is a safe and effective chemopreventive for gastric carcinogenesis based on a Mongolian gerbil model. World J. Gastroenterol. 2009, 15, 4907–4914. [Google Scholar] [CrossRef] [PubMed]
  211. Buttar, N.S.; Wang, K.K.; Leontovich, O.; Westcott, J.Y.; Pacifico, R.J.; Anderson, M.A.; Krishnadath, K.K.; Lutzke, L.S.; Burgart, L.J. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett’s esophagus. Gastroenterology 2002, 122, 1101–1112. [Google Scholar] [CrossRef] [PubMed]
  212. Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol. 2014, 24, R453–R462. [Google Scholar] [CrossRef] [PubMed]
  213. Barja, G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic. Biol. Med. 2002, 33, 1167–1172. [Google Scholar] [CrossRef]
  214. Kundu, J.K.; Surh, Y.J. Emerging avenues linking inflammation and cancer. Free Radic. Biol. Med. 2012, 52, 2013–2037. [Google Scholar] [CrossRef] [PubMed]
  215. Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428–435. [Google Scholar] [CrossRef] [PubMed]
  216. Sumimoto, H. Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS J. 2008, 275, 3249–3277. [Google Scholar] [CrossRef] [PubMed]
  217. Davtyan, T.K.; Manukyan, H.M.; Hakopyan, G.S.; Mkrtchyan, N.R.; Avetisyan, S.A.; Galoyan, A.A. Hypothalamic proline-rich polypeptide is an oxidative burst regulator. Neurochem. Res. 2005, 30, 297–309. [Google Scholar] [CrossRef] [PubMed]
  218. Okada, F.; Kobayashi, M.; Tanaka, H.; Kobayashi, T.; Tazawa, H.; Iuchi, Y.; Onuma, K.; Hosokawa, M.; Dinauer, M.C.; Hunt, N.H. The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells. Am. J. Pathol. 2006, 169, 294–302. [Google Scholar] [CrossRef] [PubMed]
  219. Nair, J.; Gansauge, F.; Beger, H.; Dolara, P.; Winde, G.; Bartsch, H. Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn’s disease, ulcerative colitis, and chronic pancreatitis. Antioxid. Redox Signal. 2006, 8, 1003–1010. [Google Scholar] [CrossRef] [PubMed]
  220. Ambs, S.; Merriam, W.G.; Bennett, W.P.; Felley-Bosco, E.; Ogunfusika, M.O.; Oser, S.M.; Klein, S.; Shields, P.G.; Billiar, T.R.; Harris, C.C. Frequent nitric oxide synthase-2 expression in human colon adenomas: Implication for tumor angiogenesis and colon cancer progression. Cancer Res. 1998, 58, 334–341. [Google Scholar] [PubMed]
  221. Wilson, K.T.; Fu, S.; Ramanujam, K.S.; Meltzer, S.J. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus and associated adenocarcinomas. Cancer Res. 1998, 58, 2929–2934. [Google Scholar] [PubMed]
  222. Sawa, T.; Ohshima, H. Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide 2006, 14, 91–100. [Google Scholar] [CrossRef] [PubMed]
  223. Okada, F.; Nakai, K.; Kobayashi, T.; Shibata, T.; Tagami, S.; Kawakami, Y.; Kitazawa, T.; Kominami, R.; Yoshimura, S.; Suzuki, K.; et al. Inflammatory cell-mediated tumour progression and minisatellite mutation correlate with the decrease of antioxidative enzymes in murine fibrosarcoma cells. Br. J. Cancer 1999, 79, 377–385. [Google Scholar] [CrossRef] [PubMed]
  224. Korantzopoulos, P.; Kolettis, T.M.; Kountouris, E.; Dimitroula, V.; Karanikis, P.; Pappa, E.; Siogas, K.; Goudevenos, J.A. Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation. Int. J. Cardiol. 2005, 102, 321–326. [Google Scholar] [CrossRef] [PubMed]
  225. Jiang, Q.; Lykkesfeldt, J.; Shigenaga, M.K.; Shigeno, E.T.; Christen, S.; Ames, B.N. γ-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation. Free Radic. Biol. Med. 2002, 33, 1534–1542. [Google Scholar] [CrossRef]
  226. Christen, S.; Woodall, A.A.; Shigenaga, M.K.; Southwell-Keely, P.T.; Duncan, M.W.; Ames, B.N. γ-Tocopherol traps mutagenic electrophiles such as NOX and complements α-tocopherol: Physiological implications. Proc. Natl. Acad. Sci. USA 1997, 94, 3217–3222. [Google Scholar] [CrossRef] [PubMed]
  227. Decker, E.A.; Xu, Z.M. Minimizing rancidity in muscle foods. Food Technol. 1998, 52, 54–59. [Google Scholar]
  228. Kim, H.J.; Kim, M.K.; Chang, W.K.; Choi, H.S.; Choi, B.Y.; Lee, S.S. Effect of nutrient intake and Helicobacter pylori infection on gastric cancer in Korea: A case-control study. Nutr. Cancer 2005, 52, 138–146. [Google Scholar] [CrossRef] [PubMed]
  229. Ohshima, H.; Tazawa, H.; Sylla, B.S.; Sawa, T. Prevention of human cancer by modulation of chronic inflammatory processes. Mutat. Res. 2005, 591, 110–122. [Google Scholar] [CrossRef] [PubMed]
  230. Lu, H.; Ouyang, W.; Huang, C. Inflammation, a key event in cancer development. Mol. Cancer Res. 2006, 4, 221–233. [Google Scholar] [CrossRef] [PubMed]
  231. Schuliga, M. NF-κB signaling in chronic inflammatory airway disease. Biomolecules 2015, 5, 1266–1283. [Google Scholar] [CrossRef] [PubMed]
  232. Tak, P.P.; Firestein, G.S. NF-κB: A key role in inflammatory diseases. J. Clin. Investig. 2001, 107, 7–11. [Google Scholar] [CrossRef] [PubMed]
  233. Solt, L.A.; May, M.J. The IκB kinase complex: Master regulator of NF-κB signaling. Immunol. Res. 2008, 42, 3–18. [Google Scholar] [CrossRef] [PubMed]
  234. Morgan, M.J.; Liu, Z.G. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011, 21, 103–115. [Google Scholar] [CrossRef] [PubMed]
  235. Blaser, H.; Dostert, C.; Mak, T.W.; Brenner, D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 2016, 26, 249–261. [Google Scholar] [CrossRef] [PubMed]
  236. Kagoya, Y.; Yoshimi, A.; Kataoka, K.; Nakagawa, M.; Kumano, K.; Arai, S.; Kobayashi, H.; Saito, T.; Iwakura, Y.; Kurokawa, M. Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J. Clin. Investig. 2014, 124, 528–542. [Google Scholar] [CrossRef] [PubMed]
  237. Peng, D.F.; Hu, T.L.; Soutto, M.; Belkhiri, A.; El-Rifai, W. Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett’s carcinogenesis. Carcinogenesis 2014, 35, 1620–1628. [Google Scholar] [CrossRef] [PubMed]
  238. Thompson, P.A.; Khatami, M.; Baglole, C.J.; Sun, J.; Harris, S.A.; Moon, E.Y.; Al-Mulla, F.; Al-Temaimi, R.; Brown, D.G.; Colacci, A.; et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 2015, 36 (Suppl. S1), S232–S253. [Google Scholar] [CrossRef] [PubMed]
  239. Schetter, A.J.; Heegaard, N.H.; Harris, C.C. Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis 2010, 31, 37–49. [Google Scholar] [CrossRef] [PubMed]
  240. Riva, F.; Bonavita, E.; Barbati, E.; Muzio, M.; Mantovani, A.; Garlanda, C. TIR8/SIGIRR is an interleukin-1 receptor/toll like receptor family member with regulatory functions in inflammation and immunity. Front. Immunol. 2012, 3, 322. [Google Scholar] [CrossRef] [PubMed]
  241. Moore, R.J.; Owens, D.M.; Stamp, G.; Arnott, C.; Burke, F.; East, N.; Holdsworth, H.; Turner, L.; Rollins, B.; Pasparakis, M.; et al. Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis. Nat. Med. 1999, 5, 828–831. [Google Scholar] [PubMed]
  242. Yoshida, G.J. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: From pathophysiology to treatment. J. Hematol. Oncol. 2017, 10, 67. [Google Scholar] [CrossRef] [PubMed]
  243. Wang, L.; Fu, H.; Nanayakkara, G.; Li, Y.; Shao, Y.; Johnson, C.; Cheng, J.; Yang, W.Y.; Yang, F.; Lavallee, M.; et al. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: A comprehensive database mining study. J. Hematol. Oncol. 2016, 9, 122. [Google Scholar] [CrossRef] [PubMed]
  244. Lin, C.; Zhang, J. Inflammasomes in inflammation-induced cancer. Front. Immunol. 2017, 8, 271. [Google Scholar] [CrossRef] [PubMed]
  245. Terlizzi, M.; Casolaro, V.; Pinto, A.; Sorrentino, R. Inflammasome: Cancer’s friend or foe? Pharmacol. Ther. 2014, 143, 24–33. [Google Scholar] [CrossRef] [PubMed]
  246. Michopoulou, A.; Rousselle, P. How do epidermal matrix metalloproteinases support re-epithelialization during skin healing? Eur. J. Dermatol. 2015, 25, 33–42. [Google Scholar] [PubMed]
  247. Knight, D. Epithelium-fibroblast interactions in response to airway inflammation. Immunol. Cell Biol. 2001, 79, 160–164. [Google Scholar] [CrossRef] [PubMed]
  248. Martin, P.; Hopkinson-Woolley, J.; McCluskey, J. Growth factors and cutaneous wound repair. Prog. Growth Factor Res. 1992, 4, 25–44. [Google Scholar] [CrossRef]
  249. Nagayasu, H.; Hamada, J.; Nakata, D.; Shibata, T.; Kobayashi, M.; Hosokawa, M.; Takeichi, N. Reversible and irreversible tumor progression of a weakly malignant rat mammary carcinoma cell line by in vitro exposure to epidermal growth factor. Int. J. Oncol. 1998, 12, 197–202. [Google Scholar] [CrossRef] [PubMed]
  250. Sun, J.; Madan, R.; Karp, C.L.; Braciale, T.J. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat. Med. 2009, 15, 277–284. [Google Scholar] [CrossRef] [PubMed]
  251. Schottelius, A.J.; Mayo, M.W.; Sartor, R.B.; Baldwin, A.S., Jr. Interleukin-10 signaling blocks inhibitor of κB kinase activity and nuclear factor κB DNA binding. J. Biol. Chem. 1999, 274, 31868–31874. [Google Scholar] [CrossRef] [PubMed]
  252. Sturlan, S.; Oberhuber, G.; Beinhauer, B.G.; Tichy, B.; Kappel, S.; Wang, J.; Rogy, M.A. Interleukin-10-deficient mice and inflammatory bowel disease associated cancer development. Carcinogenesis 2001, 22, 665–671. [Google Scholar] [CrossRef] [PubMed]
  253. Kim, S.J.; Ryu, K.J.; Hong, M.; Ko, Y.H.; Kim, W.S. The serum CXCL13 level is associated with the Glasgow Prognostic Score in extranodal NK/T-cell lymphoma patients. J. Hematol. Oncol. 2015, 8, 49. [Google Scholar] [CrossRef] [PubMed]
  254. Reinecker, H.C.; Loh, E.Y.; Ringler, D.J.; Mehta, A.; Rombeau, J.L.; MacDermott, R.P. Monocyte-chemoattractant protein 1 gene expression in intestinal epithelial cells and inflammatory bowel disease mucosa. Gastroenterology 1995, 108, 40–50. [Google Scholar] [CrossRef]
  255. Nasrallah, R.; Hassouneh, R.; Hebert, R.L. PGE2, kidney disease, and cardiovascular risk: Beyond hypertension and diabetes. J. Am. Soc. Nephrol. 2016, 27, 666–676. [Google Scholar] [CrossRef] [PubMed]
  256. Miyaura, C.; Inada, M.; Matsumoto, C.; Ohshiba, T.; Uozumi, N.; Shimizu, T.; Ito, A. An essential role of cytosolic phospholipase A2α in prostaglandin E2-mediated bone resorption associated with inflammation. J. Exp. Med. 2003, 197, 1303–1310. [Google Scholar] [CrossRef] [PubMed]
  257. Sahin, M.; Sahin, E.; Gumuslu, S. Cyclooxygenase-2 in cancer and angiogenesis. Angiology 2009, 60, 242–253. [Google Scholar] [CrossRef] [PubMed]
  258. Usman, M.W.; Luo, F.; Cheng, H.; Zhao, J.J.; Liu, P. Chemopreventive effects of aspirin at a glance. Biochim. Biophys. Acta 2015, 1855, 254–263. [Google Scholar] [CrossRef] [PubMed]
  259. IARC Working Group on the Evaluation of Cancer-Preventive Agents; International Agency for Research on Cancer. Non-Steroidal Anti-Inflammatory Drugs; International Agency for Research on Cancer: Lyon, France, 1997. [Google Scholar]
  260. Flossmann, E.; Rothwell, P.M. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: Consistent evidence from randomised and observational studies. Lancet 2007, 369, 1603–1613. [Google Scholar] [CrossRef]
  261. Cuzick, J.; Otto, F.; Baron, J.A.; Brown, P.H.; Burn, J.; Greenwald, P.; Jankowski, J.; La Vecchia, C.; Meyskens, F.; Senn, H.J.; et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An international consensus statement. Lancet Oncol. 2009, 10, 501–507. [Google Scholar] [CrossRef]
  262. Harris, R.E.; Casto, B.C.; Harris, Z.M. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J. Clin. Oncol. 2014, 5, 677–692. [Google Scholar] [CrossRef] [PubMed]
  263. Rao, P.; Knaus, E.E. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): Cyclooxygenase (COX) inhibition and beyond. J. Pharm. Pharm. Sci. 2008, 11, 81s–110s. [Google Scholar] [CrossRef] [PubMed]
  264. Fowler, T.O.; Durham, C.O.; Planton, J.; Edlund, B.J. Use of nonsteroidal anti-inflammatory drugs in the older adult. J. Am. Assoc. Nurse Pract. 2014, 26, 414–423. [Google Scholar] [CrossRef] [PubMed]
  265. Nguyen, D.M.; Richardson, P.; El-Serag, H.B. Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett’s esophagus. Gastroenterology 2010, 138, 2260–2266. [Google Scholar] [CrossRef] [PubMed]
  266. Guerra, C.; Collado, M.; Navas, C.; Schuhmacher, A.J.; Hernandez-Porras, I.; Canamero, M.; Rodriguez-Justo, M.; Serrano, M.; Barbacid, M. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 2011, 19, 728–739. [Google Scholar] [CrossRef] [PubMed]
  267. Henderson, A.J.; Ollila, C.A.; Kumar, A.; Borresen, E.C.; Raina, K.; Agarwal, R.; Ryan, E.P. Chemopreventive properties of dietary rice bran: Current status and future prospects. Adv. Nutr. 2012, 3, 643–653. [Google Scholar] [CrossRef] [PubMed]
  268. Kelloff, G.J.; Crowell, J.A.; Steele, V.E.; Lubet, R.A.; Malone, W.A.; Boone, C.W.; Kopelovich, L.; Hawk, E.T.; Lieberman, R.; Lawrence, J.A.; et al. Progress in cancer chemoprevention: Development of diet-derived chemopreventive agents. J. Nutr. 2000, 130 (Suppl. S2), S467–S471. [Google Scholar] [CrossRef]
  269. Thun, M.J.; DeLancey, J.O.; Center, M.M.; Jemal, A.; Ward, E.M. The global burden of cancer: Priorities for prevention. Carcinogenesis 2010, 31, 100–110. [Google Scholar] [CrossRef] [PubMed]
  270. Li, Z.; Zheng, Z.; Ruan, J.; Li, Z.; Tzeng, C.M. Chronic inflammation links cancer and Parkinson’s disease. Front. Aging Neurosci. 2016, 8, 126. [Google Scholar] [CrossRef] [PubMed]
  271. Levy Nogueira, M.; da Veiga Moreira, J.; Baronzio, G.F.; Dubois, B.; Steyaert, J.M.; Schwartz, L. Mechanical stress as the common denominator between chronic inflammation, cancer, and Alzheimer’s disease. Front. Oncol. 2015, 5, 197. [Google Scholar] [CrossRef] [PubMed]
  272. Pawelec, G.; Goldeck, D.; Derhovanessian, E. Inflammation, ageing and chronic disease. Curr. Opin. Immunol. 2014, 29, 23–28. [Google Scholar] [CrossRef] [PubMed]
  273. Leonard, B.E. Inflammation, depression and dementia: Are they connected? Neurochem. Res. 2007, 32, 1749–1756. [Google Scholar] [CrossRef] [PubMed]
  274. Stange, E.F.; Wehkamp, J. Recent advances in understanding and managing Crohn’s disease. F1000Res. 2016, 5, 2896. [Google Scholar] [CrossRef] [PubMed]
  275. Hajebrahimi, B.; Kiamanesh, A.; Asgharnejad Farid, A.A.; Asadikaram, G. Type 2 diabetes and mental disorders; a plausible link with inflammation. Cell. Mol. Biol. 2016, 62, 71–77. [Google Scholar] [CrossRef] [PubMed]
  276. Fougere, B.; Boulanger, E.; Nourhashemi, F.; Guyonnet, S.; Cesari, M. Chronic inflammation: Accelerator of biological aging. J. Gerontol. A Biol. Sci. Med. Sci. 2016. [Google Scholar] [CrossRef] [PubMed]
  277. Viola, J.; Soehnlein, O. Atherosclerosis—A matter of unresolved inflammation. Semin. Immunol. 2015, 27, 184–193. [Google Scholar] [CrossRef] [PubMed]
  278. Van den Hoogen, P.; van den Akker, F.; Deddens, J.C.; Sluijter, J.P. Heart failure in chronic myocarditis: A role for microRNAs? Curr. Genom. 2015, 16, 88–94. [Google Scholar] [CrossRef] [PubMed]
  279. Podolska, M.J.; Biermann, M.H.; Maueroder, C.; Hahn, J.; Herrmann, M. Inflammatory etiopathogenesis of systemic lupus erythematosus: An update. J. Inflamm. Res. 2015, 8, 161–171. [Google Scholar] [PubMed]
  280. De Souza, A.W.; de Carvalho, J.F. Diagnostic and classification criteria of Takayasu arteritis. J. Autoimmun. 2014, 48–49, 79–83. [Google Scholar] [CrossRef] [PubMed]
  281. Zhernakova, A.; Withoff, S.; Wijmenga, C. Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Nat. Rev. Endocrinol. 2013, 9, 646–659. [Google Scholar] [CrossRef] [PubMed]
  282. Monteiro, R.; Azevedo, I. Chronic inflammation in obesity and the metabolic syndrome. Mediat. Inflamm. 2010, 2010, 289645. [Google Scholar] [CrossRef] [PubMed]
  283. David, J.; Ansell, B.M.; Woo, P. Polyarteritis nodosa associated with streptococcus. Arch. Dis. Child. 1993, 69, 685–688. [Google Scholar] [CrossRef] [PubMed]
  284. Hirose, N.; Arai, Y.; Gondoh, Y.; Nakazawa, S.; Takayama, M.; Ebihara, Y.; Shimizu, K.; Inagaki, H.; Masui, Y.; Kitagawa, K.; et al. Tokyo centenarian study: Aging inflammation hypothesis. Geriatr. Gerontol. Int. 2004, 4, S182–S185. [Google Scholar] [CrossRef]
  285. Kamp, D.W.; Shacter, E.; Weitzman, S.A. Chronic inflammation and cancer: The role of the mitochondria. Oncology 2011, 25, 400–413. [Google Scholar] [PubMed]
Figure 1. Organs/tissues involved in inflammation-related cancers. The organs/tissues with inflammation induced by definitely carcinogenic agents (red circles) or by presumed carcinogenic agents (yellow circles) are sensitive to cancer development. Skin (psoriasis) and joint (rheumatoid arthritis), indicated by black circles, are resistant to inflammation-related carcinogenesis.
Figure 1. Organs/tissues involved in inflammation-related cancers. The organs/tissues with inflammation induced by definitely carcinogenic agents (red circles) or by presumed carcinogenic agents (yellow circles) are sensitive to cancer development. Skin (psoriasis) and joint (rheumatoid arthritis), indicated by black circles, are resistant to inflammation-related carcinogenesis.
Ijms 18 00867 g001
Figure 2. Causes of inflammation-related carcinogenesis. The proportion of definitely carcinogenic causes (a) or presumed carcinogenic causes (b) attributed to inflammation was derived from Table 1.
Figure 2. Causes of inflammation-related carcinogenesis. The proportion of definitely carcinogenic causes (a) or presumed carcinogenic causes (b) attributed to inflammation was derived from Table 1.
Ijms 18 00867 g002
Figure 3. Schematic mechanism of inflammation-induced cancer development. Tissue damage causes inflammatory cell infiltration (i). Leukocytes produce ROS (ii) and NO (iii) resulting in oxidative/nitrative stress (DNA damage, lipid peroxidation, protein modification and, thus, mutation). Reduction of antioxidant enzymes (iv) and antioxidants (v), which scavenge ROS, leads to enhancement of oxidative stress. A positive feedback loop between NF-κB (vi) and pro-inflammatory cytokines (vii) is necessary for inflammation to become chronic. Anti-inflammatory cytokines (viii) are downregulated in inflammation-related carcinogenesis. Chemokines (ix) recruit leukocytes into inflammatory sites. In addition to ROS, NO and pro-inflammatory cytokines, COX-2 (x) promotes cell proliferation and angiogenesis and suppresses apoptosis and immunosurveillance. Inflammation also causes DNA methylation, which results in aberrant gene expression. Ten possible chemopreventive targets are shown in the red boxes. Factors that are decreased are shown in the green boxes. Pointed arrows indicate promotion/activation while T-shaped arrows indicate suppression.
Figure 3. Schematic mechanism of inflammation-induced cancer development. Tissue damage causes inflammatory cell infiltration (i). Leukocytes produce ROS (ii) and NO (iii) resulting in oxidative/nitrative stress (DNA damage, lipid peroxidation, protein modification and, thus, mutation). Reduction of antioxidant enzymes (iv) and antioxidants (v), which scavenge ROS, leads to enhancement of oxidative stress. A positive feedback loop between NF-κB (vi) and pro-inflammatory cytokines (vii) is necessary for inflammation to become chronic. Anti-inflammatory cytokines (viii) are downregulated in inflammation-related carcinogenesis. Chemokines (ix) recruit leukocytes into inflammatory sites. In addition to ROS, NO and pro-inflammatory cytokines, COX-2 (x) promotes cell proliferation and angiogenesis and suppresses apoptosis and immunosurveillance. Inflammation also causes DNA methylation, which results in aberrant gene expression. Ten possible chemopreventive targets are shown in the red boxes. Factors that are decreased are shown in the green boxes. Pointed arrows indicate promotion/activation while T-shaped arrows indicate suppression.
Ijms 18 00867 g003
Figure 4. Natural compounds and food products have multiple chemopreventive mechanisms of action against inflammation-related carcinogenesis. The numbers of mechanisms of action of natural compounds, food products, low-molecular weight compounds, COX inhibitors and others against inflammation-related cancer development were calculated based on Table 3.
Figure 4. Natural compounds and food products have multiple chemopreventive mechanisms of action against inflammation-related carcinogenesis. The numbers of mechanisms of action of natural compounds, food products, low-molecular weight compounds, COX inhibitors and others against inflammation-related cancer development were calculated based on Table 3.
Ijms 18 00867 g004
Table 1. Cause-and-effect relationship between inflammation and its associated carcinogenesis in humans.
Table 1. Cause-and-effect relationship between inflammation and its associated carcinogenesis in humans.
Sites of Inflammation-Related CarcinogenesisCauses of Inflammation/Pathological Condition
Definitely Carcinogenic Agents (Group 1)Presumed Carcinogenic Agents (Group 2A to 3 and the Others)References
EyeHIV type 1 [8]
UV-associated skin inflammation[8]
Lip UV-associated skin inflammation[8]
Oral cavityHPV type 16 [8]
HPV type 18[8]
Lichen planus[9]
Salivary gland Sialadenitis[9]
Tongue HPV[12]
TonsilHPV type 16 [8,12]
NasopharynxEBV [8,10,12]
PharynxHPV type 16 [8]
Oropharynx HPV[12]
LarynxAsbestos [8]
HPV type 16[8]
Thyroid Chronic lymphocytic thyroiditis[14]
Hashimoto’s thyroiditis[14]
Esophagus Gastric reflux, esophagitis[9,10]
Barrett’s esophagus[10]
Barrett’s metaplasia[9]
Neisseria mucosa[15]
Neisseria sicca[15]
Neisseria subflava[15]
LungAsbestos [8]
Coal gasification [8]
Outdoor air pollution [8,10,16]
Tobacco smoke/smoking [8,10]
Interstitial pneumonia[19]
Chlamydia pneumoniae[22]
HPV type 16[23]
HIV type 1[24]
Lung mesotheliumAsbestos [8,10]
Breast HERV-K[26]
Inflammatory breast cancer [10]
StomachHelicobacter pylori [8,10,12]
Chronic atrophic gastritis[10]
LiverHBV [8,10,12]
HCV [8,10,12]
Clonorchis sinensis [8,10]
Opisthorchis viverrini [8,10]
HIV type 1[8]
Schistosoma japonicum[8,10]
α-1-anti-trypsin deficiency[28]
Bile ductClonorchis sinensis [12]
Opisthorchis viverrini [12]
Primary sclerosing cholangitis[29]
Bile acids-associated cholangitis[9]
Gall bladder Gall bladder stone-associated cholecystitis[9,10]
Primary sclerosing cholangitis[29]
Pancreaticobiliary maljunction[30]
Salmonella typhimurium[10]
Salmonella enterica serovar Typhi[31]
Pancreas Chronic pancreatitis[10]
Alcoholism-associated pancreatitis[9]
Hereditary pancreatitis[32]
Colon and Rectum Bile acids-associated coloproctitis[9]
Inflammatory bowel diseases[9,10,34]
Clostridium septicum[36]
Escherichia coli[35]
Helicobacter pylori[35]
Streptococcus bovis[35]
Streptococcus gallolyticus[37]
Schistosoma japonicum[8,10]
Bladder Schistosoma haematobium [8,10,12,38]
Urinary catheter-associated cystitis[9,39]
AnusHIV type 1 [8]
HPV type 16 [8]
HPV types 18, 33[8]
Anal fistula[40]
Testis EBV[41]
Prostate Prostatitis [42]
Proliferative inflammatory atrophy[10]
Trichomonas vaginalis[44]
OvaryAsbestos [8]
Pelvic inflammatory disease[9]
Uterine cervixHPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 [8]
HIV type 1 [8]
HPV types 26, 53, 66, 67, 68, 70, 73, 82[8]
Herpes simplex virus[10]
PenisHPV type 16 [8]
HIV types 1[8]
HPV types 18[8]
VulvaHPV type 16 [8]
HIV types 1[8]
HPV types 18, 33[8]
Lichen sclerosis[9,46]
VaginaHPV type 16 [8]
HIV types 1[8]
SkinUV-associated skin inflammation [8,10]
Chronic osteomyelitis[47]
HIV types 1[8]
HPV types 5, 8[8]
Melanoma UV-associated skin inflammation [9]
Non-melanomatous skin cancer Cutaneous HPV types[48]
Central nerve JCV[49]
Endothelium (Kaposi’s sarcoma)HIV type 1 [8,10]
KSHV [8]
Vasculature Bartonella[50]
Hodgkin’s lymphoma EBV[12]
HIV type 1[51]
Non-Hodgkin lymphoma EBV[12]
LymphomaEBV [8,10]
HCV [8]
HIV type 1 [8]
HTLV-1 [8,10]
KSHV [8]
HIV type 2[53]
Hashimoto’s thyroiditis[9]
Sjögren’s syndrome[9]
Childhood celiac disease[54]
Orbital lymphoma Chlamydia psittaci[57]
Thyroid lymphoma Hashimoto’s thyroiditis[58]
Lymphoma in the pleural cavity EBV[59]
Pyothorax-associated lymphoma EBV[60]
MALT lymphomaHelicobacter pylori [8,12]
Small-bowel lymphoma Campylobacter jejuni[61]
Cutaneous lymphoma Borrelia burgdorferi[62]
DLBC lymphoma Helicobacter pylori[12]
Adult T-cell leukemiaATL (HTLV-1) [63]
T-cell lymphoma EBV[64]
Burkitt’s lymphomaEBV [65]
B-cell lymphoma EBV[66]
Primary effusion lymphoma KSHV[67]
ATL, adult T-cell leukemia; COPD, chronic obstructive pulmonary disease; DLBC, diffuse large B-cell; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HERV-K, human endogenous retrovirus type K; HIV, 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; UV, ultraviolet.
Table 2. Animal models for inflammation-related carcinogenesis aimed at the development of chemoprevention.
Table 2. Animal models for inflammation-related carcinogenesis aimed at the development of chemoprevention.
TreatmentCarcinogenAnimalArising TumorReference
EsophagojejunostomyNoneRatEsophageal adenocarcinoma[84]
H. pylori infectionMNNGMongolian gerbilGastric adenocarcinoma[85]
DSSNoneMouseColorectal adenocarcinoma[86]
DSSAOMMouseColorectal adenocarcinoma[86]
DSSDMHMouseColorectal adenocarcinoma[87]
DSSPhIPMouseColorectal adenocarcinoma[86]
DSSNoneApcMin/+ mouseColorectal adenocarcinoma[87]
NoneNoneHBV-transgenic mouseHepatocellular carcinoma[88]
NoneDENRatHepatocellular carcinoma[89]
CCl4DENMouseHepatocellular carcinoma[90]
O. viverrini infectionNDMAHamsterCholangiocarcinoma[91]
CholedochojejunostomyN-nitrosobis(2-oxopropyl)amineHamsterBiliary carcinoma[92]
CaeruleinNoneK-ras mutated mousePancreatic ductal adenocarcinoma[93]
TPADMBAMouseSquamous cell carcinoma[94]
AOM, Azoxymethane; Apc, adenomatous polyposis coli; CCl4, carbon tetra chloride; DEN, diethylnitrosamine; DMBA, 7,12-dimethylbenz[a]-anthracene; DMH, dimethylhydrazine; DSS, dextran sulfate sodium; HBV, hepatitis B virus; H. pylori, Helicobacter pylori; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; NDMA, N-nitrosodimethylamine; O. viverrini, Opisthorchis viverrini; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine; TPA, 12-O-tetradecanoylphorbol-13-acetate.
Table 3. Chemopreventive agents against the 10 possible mechanisms of inflammation-related carcinogenesis.
Table 3. Chemopreventive agents against the 10 possible mechanisms of inflammation-related carcinogenesis.
Prevention StrategyChemopreventive Agent [Reference]Type of Agent
I. Inhibition of inflammatory cell infiltrationApocynin [143], apple oligogalactan [144], FBRA [145], Ganoderma lucidum [146], MEFA [147], MELA [147], PAG [148], γ-TmT [149]Food product
Auraptene [150], canolol [151], genistein-27 [152], geraniol [153], inotilone [154], micheliolide [155], nobiletin [156], tumerone [150], vitamin D [157]Natural compound
Hexaphosphate inositol [158], inositol [158], statin hydroxamate [159]Low-molecular weight compound
Melatonin [160]Amino acid and its derivative
Sulindac [161]COX inhibitor
Cholera-toxin [162]Protein
Oligonucleotides [163]Oligonucleotides
13-HOA [164]Fatty acid
II. Inhibition of ROSJuzen-taiho-to [165], oligonol [166], protandim [167]Food product
Auraptene [150], benzyl isothiocyanate [168], caffeine [169], crocin [170], DBM [171], digitoflavone [172], geraniol [153], GOFA/β-CD [173], menthol [174], organomagnesium [175], oxykine [176], PEITC [171], PSK [177], silibinin [178], tumerone [150], vitamin E [179], 3,3-diindolylmethane [180]Natural compound
Bismuth subnitrate [165], 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones [181]Low-molecular weight compound
Melatonin [160], N-acetylcysteine [182], selenium [182]Amino acid and its derivative
III. Suppression of iNOSEVOO [183], FBRA [184], MEFA [147], MELA [147], oligonol [166], PAG [148]Food product
Astaxanthin [185], baicalein [186], betaine [187], canolol [151], crocin [170], curcumin [188], inotilone [154], nobiletin [156], organomagnesium [175], pterostilbene [189], silibinin [178], UDCA [190], 5-OH-HxMF [191]Natural compound
Aminoguanidine [131], bezafibrate [192], GOFA-L-NAME [193], omeprazole [194], ONO-1714 [195], troglitazone [192]Low-molecular weight compound
Aspirin [196], nimesulide [192]COX inhibitor
Glutamine [197]Amino acid and its derivative
IV. Induction of antioxidant enzymesJuzen-taiho-to [165], oligonol [166], protandim [167]Food product
Crocin [170], DBM [171], digitoflavone [172], geraniol [153], GOFA/β-CD [173], menthol [174], organomagnesium [175], PEITC [171], PSK [177], 3,3-diindolylmethane [180]Natural compound
Bismuth subnitrate [165], 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones [181]Low-molecular weight compound
Melatonin [160]Amino acid and its derivative
V. AntioxidantsAuraptene [150], benzyl isothiocyanate [168], caffeine [169], geraniol [153], oxykine [176], silibinin [178], tumerone [150], vitamin E [179]Natural compound
N-acetylcysteine [182], selenium [182]Amino acid and its derivative
VI. Inactivation of NF-κBApple oligogalactan [144], EAPP [198], FBE [199], ME [199], oligonol [166], PAG [148], protandim [167]Food product
Astaxanthin [185], baicalein [186], betaine [187], crocin [170], curcumin [188], genistein-27 [152], GOFA/β-CD [173], inotilone [154], menthol [174], micheliolide [155], pterostilbene [189], silibinin [178], tricin [200], vitamin D [157], 3,3-diindolylmethane [180], 5-OH-HxMF [191]Natural compound
Cerulenin [201]Low-molecular weight compound
Glutamine [197], melatonin [160]Amino acid and its derivative
MiR-214 chemical inhibitor [202]Oligonucleotides
VII. Downregulation of pro-inflammatory cytokinesApple oligogalactan [144], EVOO [183], FBRA [145], Ganoderma lucidum [146], MEFA [147], MELA [147], oligonol [166]Food product
Astaxanthin [185], betaine [187], canolol [151], crocin [170], curcumin [188], digitoflavone [172], genistein-27 [152], GOFA/β-CD [173], isoliquiritigenin [139], micheliolide [155], organomagnesium [175], oroxylin A [203], pterostilbene [189], silibinin [178], tricin [200], triptolide [204], resveratrol [205], UDCA [190], vitamin D [157]Natural compound
Cerulenin [201], GOFA-L-NAME [193], NT1014 [206], omeprazole [194], statin hydroxamate [159], 3-aroylmethylene-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-ones [181], 5-aza-dC [207]Low-molecular weight compound
Glutamine [197], melatonin [160]Amino acid and its derivative
Aspirin [196]COX inhibitor
Cholera-toxin [162], α-lactalbumin [208]Protein
Oligonucleotides [163]Oligonucleotides
Eicosapentaenoic acid-free fatty acid [209]Fatty acid
VIII. Upregulation of anti-inflammatory cytokinesPSK [177]Natural compound
Cholera-toxin [162]Protein
IX. Downregulation of chemokinesFBRA [145]Food product
Auraptene [150], tumerone [150], vitamin D [157]Natural compound
Statin hydroxamate [159]Low-molecular weight compound
Glutamine [197]Amino acid and its derivative
Oligonucleotides [163]Oligonucleotides
X. Inhibition of COX-2EVOO [183], FBRA [184], Ganoderma lucidum [146], MEFA [147], MELA [147], oligonol [166], PAG [148], γ-TmT [149]Food product
Astaxanthin [185], betaine [187], canolol [151], crocin [170], curcumin [188], geraniol [153], inotilone [154], isoliquiritigenin [139], menthol [174], nobiletin [156], organomagnesium [175], pterostilbene [189], resveratrol [205], silibinin [178], 3,3-diindolylmethane [180], 5-OH-HxMF [191]Natural compound
Bezafibrate [192], cerulenin [201], GOFA-L-NAME [193], omeprazole [194], statin hydroxamate [159], troglitazone [192]Low-molecular weight compound
Glutamine [197], melatonin [160]Amino acid and its derivative
Aspirin [196], celecoxib [210], MF-tricyclic [211], nimesulide [192], sulindac [161]COX inhibitor
α-lactalbumin [208]Protein
Oligonucleotides [163]Oligonucleotides
Eicosapentaenoic acid-free fatty acid [209]Fatty acid
COX-2, cyclooxygenase-2; DBM, dibenzoylmethane; EAPP, ethanol extracts from the aerial parts of A. princeps Pampanini cv. Sajabal; EVOO, extra virgin olive oil; FBE, fruiting body extract; FBRA, fermented brown rice and rice bran with Aspergillus oryzae; GOFA-L-NAME, 4′-geranyloxyferulic acid-N(omega)-nitro-l-arginine methyl ester; GOFA/β-CD, 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid/β-cyclodextrin; iNOS, inducible nitric oxide synthase; ME, mycelia extract; MEFA, methanol extracts of the fruit of A. communis; MELA, methanol extract of the leaf of A. communis; miR, microRNA; γ-TmT, γ-tocopherol-rich mixture of tocopherols; PAG, processed Aloe vera gel; PEITC, phenethyl isothiocyanate; PSK, polysaccharide K; ROS, reactive oxygen species; UDCA, ursodeoxycholic acid; 13-HOA, (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid; 5-OH-HxMF, 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone.

Share and Cite

MDPI and ACS Style

Kanda, Y.; Osaki, M.; Okada, F. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction. Int. J. Mol. Sci. 2017, 18, 867.

AMA Style

Kanda Y, Osaki M, Okada F. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction. International Journal of Molecular Sciences. 2017; 18(4):867.

Chicago/Turabian Style

Kanda, Yusuke, Mitsuhiko Osaki, and Futoshi Okada. 2017. "Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction" International Journal of Molecular Sciences 18, no. 4: 867.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop