Inflammation-induced Carcinogenesis Research Articles

205 Discovery and Development of Bardoxolone Methyl, an Antioxidant Inflammation Modulator (AIM) Targeting the KEAP1-NRF2 Pathway

DISCOVERY AND DEVELOPMENT OF BARDOXOLONE METHYL, AN ANTIOXIDANT INFLAMMATION MODULATOR (AIM) TARGETING THE KEAP1-NRF2 PATHWAY Colin J. Meyer, W. Christian Wigley, Deborah A. Ferguson, J. Warren Huff, Robin Kral, Karen T. Liby, Michael B. Sporn Reata Pharmaceuticals, Inc., Irving, TX, USA; Dartmouth Medical School, Hanover, NH, USA. Bardoxolone methyl and related analogs in the AIM class are the most potent known inducers of the Keap1-Nrf2 pathway. AIMs were discovered through an approach to identify novel molecules to inhibit inflammation-induced carcinogenesis. Oleanolic acid, a triterpenoid natural product, was selected as the initial scaffold due to its weak antiinflammatory and anti-carcinogenic activity. Synthetic derivatives were evaluated by measuring suppression of NO production in activated macrophages; bardoxolone was one of the most potent analogs (IC50=0.11 nM). Biochemical assays established that bardoxolone directly interacts with regulatory cysteine residues on Keap1. Activation of Keap1 promotes accumulation of Nrf2 in the nucleus, inducing transcription of genes that increase antioxidant capacity, induce glutathione synthesis, and conjugate and export potentially harmful molecules from the cell. In addition, Keap1 activation suppresses the pro-inflammatory activity of NF-κB. Bardoxolone protects against pro-inflammatory stimuli in vitro and in vivo in an Nrf2-dependent manner. Bardoxolone and related analogs have also been shown to improve endothelial dysfunction, suppress mesangial cell contraction, and increase inulin clearance in preclinical studies. Open-label clinical trials of bardoxolone resulted in substantial improvements in measures of kidney function in most patients. In a recent double-blind, randomized trial, placebo-controlled trial, treatment with bardoxolone for 24 weeks in patients with Stage 3b/4 chronic kidney disease and type 2 diabetes resulted in a large increase in eGFR of 10.1±1.1 mL/min/1.73m relative to no change in the placebo group (p<0.001). Significant improvements were also noted in other measured of kidney function, including blood urea nitrogen, serum phosphorus, and serum uric acid relative to placebo. Bardoxolone has been well tolerated to date. A Phase 3 study (BEACON) is being initiated in the same population to measure time to a composite of 50% decline in eGFR, renal replacement therapy, or death.

Toll-Like Receptor 4 Activation in Cancer Progression and Therapy

Cancer immunotherapy has been the focus of intense research since the late 19th century when Coley observed that bacterial components can contribute to cancer regression by eliciting an antitumor immune response. Successful activation and maturation of tumor-specific immune cells is now known to be mediated by bacterial endotoxin, which activates Toll-like receptor 4 (TLR4). TLR4 is expressed on a variety of immune as well as tumor cells, but its activation can have opposing effects. While TLR4 activation can promote antitumor immunity, it can also result in increased tumor growth and immunosuppression. Nevertheless, TLR4 engagement by endotoxin as well as by endogenous ligands represents notable contribution to the outcome of different cancer treatments, such as radiation or chemotherapy. Further research of the role and mechanisms of TLR4 activation in cancer may provide novel antitumor vaccine adjuvants as well as TLR4 inhibitors that could prevent inflammation-induced carcinogenesis.

Abstract PR-02: STAT2 contributes to promotion of colorectal and skin carcinogenesis

Abstract STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction pathway and well described for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, STAT2 is unique as IFNs are the only cytokines known to date to induce its activation. Given the inflammatory and antiproliferative dual nature of IFNs, our initial hypothesis was that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory microenvironment. In contradiction to our hypothesis, deletion of STAT2 inhibited rather than promoted AOM/DSS-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. This protective effect was not restricted to the colon as deletion of STAT2 also inhibited DMBA/TPA-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of proinflammatory mediators. Deletion of STAT2 decreased AOM/DSS-induced expression and release of proinflammatory mediators such as interleukin 6 and CCL2 and decreased interleukin-6 release from skin carcinoma cells, which in turn decreased STAT3 activation. Therefore, our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of proinflammatory mediators, which then activate the oncogenic STAT3 signaling pathway. This talk is also presented as Poster A27. Citation Information: Cancer Prev Res 2010;3(12 Suppl):PR-02.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

The cytokines lymphotoxin (LT) alpha, beta and their receptor (LTbetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTbetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTbetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTbetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTbetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTbetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.

Myeloperoxidase-induced Genomic DNA-centered Radicals

Myeloperoxidase (MPO) released by activated neutrophils can initiate and promote carcinogenesis. MPO produces hypochlorous acid (HOCl) that oxidizes the genomic DNA in inflammatory cells as well as in surrounding epithelial cells. DNA-centered radicals are early intermediates formed during DNA oxidation. Once formed, DNA-centered radicals decay by mechanisms that are not completely understood, producing a number of oxidation products that are studied as markers of DNA oxidation. In this study we employed the 5,5-dimethyl-1-pyrroline N-oxide-based immuno-spin trapping technique to investigate the MPO-triggered formation of DNA-centered radicals in inflammatory and epithelial cells and to test whether resveratrol blocks HOCl-induced DNA-centered radical formation in these cells. We found that HOCl added exogenously or generated intracellularly by MPO that has been taken up by the cell or by MPO newly synthesized produces DNA-centered radicals inside cells. We also found that resveratrol passed across cell membranes and scavenged HOCl before it reacted with the genomic DNA, thus blocking DNA-centered radical formation. Taken together our results indicate that the formation of DNA-centered radicals by intracellular MPO may be a useful point of therapeutic intervention in inflammation-induced carcinogenesis.

Epimorphin deletion protects mice from inflammation-induced colon carcinogenesis and alters stem cell niche myofibroblast secretion

Epithelial-mesenchymal interactions regulate normal gut epithelial homeostasis and have a putative role in inflammatory bowel disease and colon cancer pathogenesis. Epimorphin is a mesenchymal and myofibroblast protein with antiproliferative, promorphogenic effects in intestinal epithelium. We previously showed that deletion of epimorphin partially protects mice from acute colitis, associated with an increase in crypt cell proliferation. Here we explored the potential therapeutic utility of modulating epimorphin expression by examining the effects of epimorphin deletion on chronic inflammation-associated colon carcinogenesis using the azoxymethane/dextran sodium sulfate (AOM/DSS) model. We found that mice in which epimorphin expression was absent had a marked reduction in incidence and extent of colonic dysplasia. Furthermore, epimorphin deletion in myofibroblasts altered the morphology and growth of cocultured epithelial cells. Loss of epimorphin affected secretion of soluble mesenchymal regulators of the stem cell niche such as Chordin. Importantly, IL-6 secretion from LPS-treated epimorphin-deficient myofibroblasts was completely inhibited, and stromal IL-6 expression was reduced in vivo. Taken together, these data show that epimorphin deletion inhibits chronic inflammation-associated colon carcinogenesis in mice, likely as a result of increased epithelial repair, decreased myofibroblast IL-6 secretion, and diminished IL-6-induced inflammation. Furthermore, we believe that modulation of epimorphin expression may have therapeutic benefits in appropriate clinical settings.

Ganoderma lucidum suppresses colon carcinogenesis and inflammation

Medicinal mushroom Ganoderma lucidum, well recognized natural product that have been used in the traditional Chinese medicine, is currently used as a popular dietary supplement. Here, we show that an oral application of G. lucidum triterpene extract (GLT) suppressed colon carcinogenesis induced by the food‐borne carcinogen (2‐Amino‐1‐methyl–6‐phenylimidazol[4,5‐b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. PhIP and DSS induced formation of colonic tumors, whereas GLT treatment significantly decreased the number of tumors. Furthermore, GLT suppressed focal hyperplasia and aberrant crypt foci (ACF) formation. These anti‐proliferative effects of GLT were confirmed by the decreased staining with Ki‐67 in colon tissues. PhIP/DSS‐induced colon inflammation was demonstrated by the significant shortening of the large intestine, whereas GLT treatment reversed the shortening of colon lengths to the levels comparable to the control group. Moreover, PhIP/DSS‐induced infiltration of macrophages was significantly reduced in colon tissue in animals treated with GLT. Our data suggest that GLT could be considered as an alternative dietary approach for the suppression of the food‐borne carcinogen‐ and inflammation‐induced colon carcinogenesis.Supported by P50 AT00477 from NCCAM and the NIH Office of Dietary Supplements.

Nrf2-Keap1 Signaling as a Potential Target for Chemoprevention of Inflammation-Associated Carcinogenesis

Persistent inflammatory tissue damage is causally associated with each stage of carcinogenesis. Inflammation-induced generation of reactive oxygen species, reactive nitrogen species, and other reactive species not only cause DNA damage and subsequently mutations, but also stimulate proliferation of initiated cells and even metastasis and angiogenesis. Induction of cellular cytoprotective enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase, superoxide dismutase, glutathione-S-transferase, etc.) has been shown to mitigate aforementioned events implicated in inflammation-induced carcinogenesis. A unique feature of genes encoding these cytoprotective enzymes is the presence of a cis-acting element, known as antioxidant response element (ARE) or electrophile response element (EpRE), in their promoter region. A stress-responsive transcription factor, nuclear factor erythroid-2-related factor-2 (Nrf2), initially recognized as a key transcriptional regulator of various cytoprotective enzymes, is known to play a pivotal role in cellular defense against inflammatory injuries. Activation of Nrf2 involves its release from the cytosolic repressor Kelch-like ECH-associated protein-1 (Keap1) and subsequent stabilization and nuclear localization for ARE/EpRE binding. Genetic or pharmacologic inactivation of Nrf2 has been shown to abolish cytoprotective capability and to aggravate experimentally induced inflammatory injuries. Thus, Nrf2-mediated cytoprotective gene induction is an effective strategy for the chemoprevention of inflammation-associated carcinogenesis.

Increased expression and cellular localization of spermine oxidase in ulcerative colitis and relationship to disease activity

Polyamines are important in cell growth and wound repair, but have also been implicated in inflammation-induced carcinogenesis. Polyamine metabolism includes back-conversion of spermine to spermidine by the enzyme spermine oxidase (SMO), which produces hydrogen peroxide that causes oxidative stress. In ulcerative colitis (UC), levels of spermine are decreased compared to spermidine. Therefore, we sought to determine if SMO is involved in UC. Colon biopsies and clinical information from subjects undergoing colonoscopy for evaluation of UC or colorectal cancer screening were utilized from 16 normal controls and 53 UC cases. Histopathologic disease severity was graded and the Mayo Disease Activity Index (DAI) and endoscopy subscore assessed. SMO mRNA expression was measured in frozen biopsies by TaqMan-based real-time polymerase chain reaction (PCR). Formalin-fixed tissues were used for SMO immunohistochemistry. There was a 3.1-fold upregulation of SMO mRNA levels in UC patients compared to controls (P = 0.044), and a 3.7-fold increase in involved left colon versus paired uninvolved right colon (P < 0.001). With worsening histologic injury in UC there was a progressive increase in SMO staining of mononuclear inflammatory cells. There was a similar increase in SMO staining with worsening endoscopic disease severity and strong correlation with the DAI (r = 0.653, P < 0.001). Inflammatory cell SMO staining was increased in involved left colon versus uninvolved right colon. SMO expression is upregulated in UC tissues, deriving from increased levels in mononuclear inflammatory cells. Dysregulated polyamine homeostasis may contribute to chronic UC by altering immune responses and increasing oxidative stress.

Regulation of proliferation, apoptosis and cell cycle in gastrointestinal disorders

Carcinogenesis is a multifactorial process representing the accumulation of acquired and genetic defects, and it has become apparent that many gastrointestinal cancers originate from a state of chronic inflammation. Advances in the field of inflammation-induced carcinogenesis over the past several years have focused on the creation of agonists or antagonists of cytokines and pathways regulating proliferation and apoptosis, and include advances such as the discovery of pharmacological inhibitors of the histone deacetylase (HDAC) family of transcriptional co-repressors, which induce apoptosis of neoplastic cells; discovery of natural products, such as curcumin, which have been shown to regulate cytokine expression; and further investigation into the role of annexin A1, a downstream mediator of glucocorticoid action, in the regulation of inflammation, to name a few.

Two Cases of Bovine Sarcoma in Clinically Long-Standing Lesions

Histopathological examination of clinically long-standing lesions with durations of one year or more in the extremities of two cattle revealed the presence of sarcomas with distant metastases. In case 1, neoplastic cells were fusiform to pleomorphic, stained for no specific differentiation markers, and diagnosed as undifferentiated sarcoma. Neoplastic growth in case 2 was composed of spindle to histiocytoid cells and a significant number of multinucleated giant cells, both of which were immunoreactive to histiocyte markers, and diagnosed as giant cell malignant fibrous histiocytoma. Neoplastic cells of both cases were immunohistochemically positive for nitric oxide-related antigens, which were recognized as markers of inflammation-induced carcinogenesis in human and laboratory animals.

Inflammation and Stem Cells in Gastrointestinal Carcinogenesis

Chronic inflammation-induced carcinogenesis is a commonly accepted entity and is frequently seen within the gastrointestinal tract, although the underlying mechanisms remain unclear. Alterations in specific oncogenes and tumor suppressor genes are known to be responsible for malignant transformation. Nevertheless, the inflammatory microenvironment classically affects tumor promotion in its role as an altered stem cell niche and can also affect tumor initiation and tumor progression. The origin of the tumor cells is often attributed to stem cells, a unique subpopulation within tumors that possess the ability to initiate tumor growth and sustain self-renewal, as well as is largely responsible for their metastatic potential. Here, we review the link between inflammation and gastrointestinal carcinogenesis and the relationship between stem cells and cancer stem cells.

Inflammation as the primary aetiological agent of human prostate cancer: A stem cell connection?

Inflammation has been implicated for some time as a potential aetiological agent in human prostate cancer. Viral and bacterial infections or even chemical carcinogens such as those found in cooked meat have been proposed as the inflammatory stimuli, but the mechanism of cancer induction is unknown. Recent information about gene expression patterns in normal and malignant epithelial stem cells from human prostate provides a new hypothesis for inflammation-induced carcinogenesis. The hypothesis states that in the stem cells located in the basal cell compartment of the prostate, activated prostate epithelial stem cells acquire a survival advantage, by expressing one of more of the same cytokines such as IL6. The establishment of one or more autocrine signalling loops results in an expansion of these cells in the absence of inflammation, as a potential first stage in the development of the tumour.

Nuclear localization of human spermine oxidase isoforms – possible implications in drug response and disease etiology

The recent discovery of the direct oxidation of spermine via spermine oxidase (SMO) as a mechanism through which specific antitumor polyamine analogues exert their cytotoxic effects has fueled interest in the study of the polyamine catabolic pathway. A major byproduct of spermine oxidation is H2O2, a source of toxic reactive oxygen species. Recent targeted small interfering RNA studies have confirmed that SMO-produced reactive oxygen species are directly responsible for oxidative stress capable of inducing apoptosis and potentially mutagenic DNA damage. In the present study, we describe a second catalytically active splice variant protein of the human spermine oxidase gene, designated SMO5, which exhibits substrate specificities and affinities comparable to those of the originally identified human spermine oxidase-1, SMO/PAOh1, and, as such, is an additional source of H2O2. Importantly, overexpression of either of these SMO isoforms in NCI-H157 human non-small cell lung carcinoma cells resulted in significant localization of SMO protein in the nucleus, as determined by confocal microscopy. Furthermore, cell lines overexpressing either SMO/PAOh1 or SMO5 demonstrated increased spermine oxidation in the nucleus, with accompanying alterations in individual nuclear polyamine concentrations. This increased oxidation of spermine in the nucleus therefore increases the production of highly reactive H2O2 in close proximity to DNA, as well as decreases nuclear spermine levels, thus altering the protective roles of spermine in free radical scavenging and DNA shielding, and resulting in an overall increased potential for oxidative DNA damage in these cells. The results of these studies therefore have considerable significance both with respect to targeting polyamine oxidation as an antineoplastic strategy, and in regard to the potential role of spermine oxidase in inflammation-induced carcinogenesis.

Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis.

Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3'-methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88-/- mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNF-deficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model.

Physiological activities of carbon monoxide‐releasing molecules: Ça ira

In this issue of British Journal of Pharmacology, Megías and colleagues demonstrate how preincubation of human colonic Caco-2 cells with CORM-2, a carbon monoxide releasing molecule (CO-RM), reduces the expression of inducible nitric oxide synthase, interleukin (IL)-6 and IL-8 caused by proinflammatory cytokines. A role for IL-6 in the regulation of metalloproteinase (MMP)-7 expression by CORM-2 is described. However, it is the demonstration that CORM-2 inhibits MMP-7 or matrilysin expression, which is most intriguing as this small MMP has been implicated in carcinogenesis. Thus, CO-RMs appear to now possess chemoprotective properties and, in this particular case, may influence inflammation-induced colon carcinogenesis via modulation of nuclear factors participating in the transcription of genes implicated in the development of intestinal inflammation and cancer. This report opens yet another door for research involving these exciting molecules and it is now clear that further discoveries of the beneficial properties of CO-RMs will go on.

Inflammation, Cancer and Chemoresistance: Taking Advantage of the Toll‐Like Receptor Signaling Pathway

The association between chronic inflammation and cancer has long been observed. Furthermore, NF-kappaB activation and the subsequent production of cytokines, chemokines, growth factors, and antiapoptotic proteins has been found to be involved in cancer progression and chemoresistance. However, the signals inducing NF-kappaB in cancer cells are still not well understood. Here, we reviewed the association between chronic inflammation and cancer, the role of NF-kappaB and its inhibitors as potential anticancer drugs, and Toll-like receptors as possible signal initiators for NF-kappaB activation and inflammation-induced carcinogenesis and chemoresistance. Furthermore, we propose that, the stimulation of Toll-like receptors by microbial components and/or endogenous ligands may represent the initial signal promoting a proinflammatory environment that will enhance tumor growth and chemoresistance.

Tumor Necrosis Factor-α Increases Reactive Oxygen Species by Inducing Spermine Oxidase in Human Lung Epithelial Cells: A Potential Mechanism for Inflammation-Induced Carcinogenesis

Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-alpha (TNF-alpha) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-alpha exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-alpha-treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H(2)O(2). Inhibition of TNF-alpha-induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H(2)O(2) by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers.

Guanine Nitration in Idiopathic Pulmonary Fibrosis and Its Implication for Carcinogenesis

Nitric oxide (NO)-induced nitrative stress of nucleic acids, as evidenced by guanine nitration, appears to be involved in inflammation-induced carcinogenesis. A high incidence of lung cancer in idiopathic pulmonary fibrosis (IPF) is the major reason for poor prognosis in patients with IPF. We immunohistochemically analyzed the formation and localization of 8-nitroguanine in lung tissues from control subjects, patients with IPF, and patients with lung cancer. Immunohistochemical analysis of control smoker and nonsmoker lungs showed weak immunoreactivity for 8-nitroguanine, mainly in cytoplasm of bronchial epithelial cells. In addition to the bronchial epithelial cells, metaplastic regenerated epithelial cells overlying dense fibrotic lesions in IPF showed strong 8-nitroguanine staining in the cytoplasm. The staining in these metaplastic cells colocalized with staining of inducible and endothelial NO synthases and 8-oxodeoxyguanosine, as evidenced by double-immunostaining analysis. Confocal and immunoelectron microscopy revealed localization of 8-nitroguanine in metaplastic epithelial cytoplasm, mostly in mitochondria. Appreciable 8-nitroguanine immunostaining was also observed in both nuclei and cytoplasm of malignant epithelial cells in squamous cell carcinoma. No significant difference was found in the epithelial 8-nitroguanine formation between control smokers and nonsmokers, but much higher guanine nitration was observed in patients with IPF than in control subjects and patients with lung cancer, via a quantitative immunofluorescence image analysis. The present study indicates that not only oxidative stress but also nitrative stress induced by NO may participate in the pathogenesis of epithelial cell damage and aberrant regeneration occurring in IPF. Thus, guanine nitration may be a major risk factor for lung cancer development in IPF.

Molecular Mechanisms of Inflammation-Induced Carcinogenesis

Chronic inflammation has been thought as the major risk factor for various types of human cancer. The International Agency for Research on Cancer (IARC) has estimated that approximately one-fifth of cancer cases worldwide is attributable to infectious/inflammatory diseases. While we fundamentally understand that persistent inflammation plays a role in carcinogenesis, recent advances in the molecular study of the mechanisms have revealed that reactive oxygen and nitrogen species, harmful endogenous genotoxic substances, produced by inflammatory cells are largely involved in the carcinogenic process. In this article, we review the instances demonstrating the definite link between inflammation and cancer, and shed light on the molecular mechanisms proved to be responsible for the inflammation-based carcinogenesis.