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Chronic Inflammation and CancerPublished on Psychiatric Times(http://www.psychiatrictimes.com)

Chronic Inflammation and CancerReview Article [1] | January 31, 2002By Emily Shacter, PhD [2] and Sigmund A. Weitzman, MD [3]

A substantial body of evidence supports the conclusion that chronic inflammation can predispose anindividual to cancer, as demonstrated by the association between chronic inflammatory boweldiseases and the increased risk of colon carcinoma. Chronic inflammation is caused by a variety offactors, including bacterial, viral, and parasitic infections, chemical irritants, and nondigestibleparticles.

ABSTRACT: A substantial body of evidence supports the conclusion that chronicinflammation can predispose an individual to cancer, as demonstrated by the associationbetween chronic inflammatory bowel diseases and the increased risk of colon carcinoma.Chronic inflammation is caused by a variety of factors, including bacterial, viral, andparasitic infections, chemical irritants, and nondigestible particles. The longer theinflammation persists, the higher the risk of associated carcinogenesis. This reviewdescribes some of the underlying causes of the association between chronic inflammationand cancer. Inflammatory mediators contribute to neoplasia by inducing proneoplasticmutations, adaptive responses, resistance to apoptosis, and environmental changes suchas stimulation of angiogenesis. All these changes confer a survival advantage to asusceptible cell. In this article, we discuss the contribution of reactive oxygen andnitrogen intermediates, prostaglandins, and inflammatory cytokines to carcinogenesis. Athorough understanding of the molecular basis of inflammation-associated neoplasia andprogression can lead to novel approaches to the prevention and treatment of cancer.

Chronic inflammation may be a causative factor in a variety of cancers. In general, the longer theinflammation persists, the higher the risk of cancer. Hence, acute inflammation, such as occurs inresponse to a transient infection, is not regarded as a risk factor for the development of neoplasia,although many of the same molecular mediators are generated in both acute and chronicinflammation. In general, inflammatory leukocytes such as neutrophils, monocytes, macrophages,and eosinophils provide the soluble factors that are thought to mediate the development ofinflammation-associated cancer, although other cells, including the cancer cells themselves, alsoparticipate.Inflammatory mediators include metabolites of arachidonic acid, cytokines, chemokines, and freeradicals. Chronic exposure to these mediators leads to increased cell proliferation, mutagenesis,oncogene activation, and angiogenesis. The ultimate result is the proliferation of cells that have lostnormal growth control. Animal models provide experimental evidence that chronic inflammation canpromote cancer and further insights into possible mechanisms.This review will summarize the clinical association between chronic inflammation and cancer and willdescribe the inflammatory factors and pathways that are thought to be proneoplastic. Emphasis willbe placed on examining the role of the reactive oxygen and nitrogen intermediates, cytokines, andprostaglandins.

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Inflammatory Conditions That Predispose to Cancer TABLE 1

Chronic Inflammatory Conditions That Predispose Susceptible Cells to Neoplastic Transformation

A wide array of chronic inflammatory conditions predispose susceptible cells to neoplastictransformation (Table 1).[1-17] Most of the resulting tumors are of epithelial cell origin (carcinomas).The most widely studied and best established of these links are colon carcinoma associated withinflammatory bowel disease (chronic ulcerative colitis and Crohn’s disease), esophagealadenocarcinoma associated with reflux esophagitis (Barrett’s esophagus), hepatitis predisposing toliver cancer, schistosomiasis causing an increased risk of bladder and colon carcinomas, and chronic Helicobacter infection leading to cancer of the stomach. Some increase in the incidence oflymphoma is also seen, particularly mucosa-associated lymphoid tissue (MALT) lymphoma.Inflammatory Bowel Disease and Colon CarcinogenesisMuch of our understanding of the association between chronic inflammation and cancer is illustratedthrough inflammatory bowel disease and colon carcinogenesis. Patients with either chroniculcerative colitis or Crohn’s disease have a five- to sevenfold increased risk of developing colorectalcarcinoma.[18] It is generally thought that the colitis must persist for at least 8 years to significantlyincrease the risk of cancer.[2] Neoplasia generally appears after a median duration of approximately15 years. Increased cancer incidence is associated with increased duration of the inflammation.Like other forms of cancer, colon carcinogenesis is a multistage process. It begins with focalproliferation of dysplastic cells, the formation of benign adenomatous polyps, and potentialprogression to malignant adenocarcinomas.[19] Mutations in oncogenes and tumor-suppressorgenes (p53, APC, and Ki-ras) are found in a high percentage of colon cancers.[20] The molecularnature of the mutations differs in colon cancers associated with chronic colitis compared to sporadicand familial colon carcinoma, suggesting different mechanisms of mutagenesis. The cancers thatdevelop are found predominantly at the sites of the inflammation and not at distant sites.[2] Chronicintake of anti-inflammatory drugs decreases the incidence of colon carcinogenesis associated withinflammatory bowel diseases (see below).Chronic InflammationAnimal models demonstrate experimentally that chronic inflammation predisposes to thedevelopment of various forms of cancer. For example, marmosets have a high incidence ofspontaneous colitis and a high incidence of colon cancer as well. Skin cancer is induced byad-ministration of carcinogens such as dimethylbenzanthracine (DMBA) followed by repeatedadministration of tumor promoters such as phorbol myristate acetate (PMA) or benzoyl peroxide,which induce inflammation and the production of various inflammatory mediators.[21]Intraperitoneal introduction of mineral oils (eg, pristane) or plastic discs into BALB/c mice promotesthe formation of chronic granulomatous tissue and the development of plasmacytomas.[22]In these animal models, the tumors generally arise in the inflammatory tissue, indicating that localinflammatory mediators are responsible for their development. In some cases, there is strongevidence suggesting a genetic basis for the susceptibility to tumor development. For example, in themouse plasmacytoma model, BALB/c mice are uniquely susceptible to developing plasma cell tumors

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in response to pristane, whereas most other strains are not. Similarly, SENCAR mice are uniquelysusceptible to developing skin tumors in response to DMBA and PMA. These findings provide a basisfor identifying critical genes and factors that contribute to tumor development and may explain why,for example, some individuals with chronic inflammatory conditions and carcinogen exposure (eg,smokers) develop cancer while others do not.As shown in Table 1, the types of chronic inflammation that lead to cancer are varied. In some cases,the progenitors of the inflammation are known. These include chronic bacterial and parasiticinfections, chemical irritants, and nondigestible particles. In other cases, the underlying cause of thechronic inflammation is unknown. This is true for inflammatory bowel disease, sialadenitis, and lichensclerosis. Some of the known chronic inflammatory agents will be described below. Of these,parasitic infections are perhaps the best described. It seems that any parasitic infection that persistsor recurs over many years can predispose to cancer. Thus, bacterial, viral, and parasitic infectionscan all lead to cancer if left unchecked.Bacterial InfectionsThe strongest association between chronic bacterial infection and the development of cancerinvolves the organism Helicobacter pylori, which is associated with at least a twofold increased riskof adenocarcinoma of the stomach.[23,24] In addition, H pylori infection is thought to increase theincidence of MALT lymphoma.[25] Strong experimental evidence that Helicobacter infection iscarcinogenic comes from studies showing that gerbils infected with H pylori develop active chronicgastritis followed by a high incidence of gastric adenocarcinoma. Helicobacter infection in humans isalways accompanied by mucosal inflammation (gastritis) with an influx of lymphocytes, plasma cells,and neutrophils. The robust immune response to H pylori generally fails to clear the infection, thusresulting in a chronic inflammatory response thought to be a key element of the carcinogenic activityof the bacterium.Unless treated, H pylori infection and the associated gastritis persist for decades. Eradication of Hpylori infection with antibiotics may also eliminate the excess risk for cancer, but this has not yetbeen established.Parasitic InfectionsSeveral parasitic infections are known to increase the risk of cancer. Schistosomiasis is prevalentprimarily in Third World countries and is difficult to treat because contaminated water supplies leadto reinfection.[10] Chronic schistosomiasis induces cystitis and fibrosis and increases the incidenceof carcinoma of the bladder, liver, and rectum, and follicular lymphoma of the spleen, with differentstrains of the parasites infecting specific organs and leading to the various cancers.[10] Liver flukes(Opisthorchis and Clonarchis), introduced by eating raw fish, infect the bile duct and lead to chroniccholangitis associated with an increased incidence of cholangiocarcinoma.[11] Chronic infection andinflammatory diseases may also contribute to the development of Hodgkin’s disease andnon-Hodgkin’s lymphoma.[26] Reference Guide Therapeutic Agents

Mentioned in This Article Aspirin

Cisplatin

Doxorubicin

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Etoposide

Fluorouracil (5-FU)

Indomethacin

Sulindac

Ursodiol (Actigall)

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Viral InfectionsMany different viruses cause an increased incidence of cancer. Those most commonly associatedwith chronic inflammation are the hepatitis B and C viruses, which lead to chronic active hepatitisand hepatocellular carcinoma.[13] Epstein-Barr virus (EBV) is associated with B-cell non-Hodgkin’slymphoma, and may contain a chronic inflammatory component.[27] Other viral infections can alsoincrease the incidence of cancer, but the role of inflammatory mediators is less clear. For example,the human papillomavirus, herpes simplex virus 2, and cytomegalovirus have been implicated incervical and other carcinomas.[28] Among RNA retroviruses, the human immunodeficiency virus(HIV) predisposes to the development of non-Hodgkin’s lymphoma, squamous cell carcinomas, andKaposi’s sarcoma,[29] while the human T-cell lymphoma virus causes adult T-cell leukemia.Unlike the other parasitic infections described here, viruses implicated in inducing neoplasia directlyinfect the cells that ultimately undergo neoplastic transformation. Hence, it is difficult to determinewhether these agents act by causing a chronic inflammatory condition, by directly transforming thecells that they infect, or both. Most of these viruses induce chronic increased proliferation of theinfected cells, thus predisposing to neoplastic transformation (see below). For example, EBV causessustained proliferation of peripheral B lymphocytes, but when coupled with a secondary mutationcan result in malignant transformation, such as occurs with the chromosomal translocations thatactivate the c-myc oncogene in Burkitt’s lymphoma. The hepatitis viruses are thought to give rise tohepatocellular carcinoma by causing liver damage and regeneration together with the generation ofsecondary inflammatory mediators.[13]Noninfectious Causes of Chronic InflammationVarious noninfectious agents also cause chronic inflammation associated with an increased risk ofcancer. For example, esophageal reflux causes chronic exposure of the esophageal epidermis toirritation by gastric acids. This leads to reflux esophagitis, or Barrett’s esophagus, and subsequentdevelopment of esophageal carcinoma.[12]Excess fecal bile acids in patients with primary sclerosing cholangitis and ulcerative colitis are

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associated with an increased risk of colorectal carcinoma. A recent publication demonstrated thatursodiol (Actigall), a drug that reduces the colonic levels of deoxycholate and other bile acids (usedto treat cholangitis), significantly reduces the incidence of neoplasia.[30] Chronic irritation of theliver by alcohol causes cirrhosis and hepatocellular carcinoma.[31]Nondigestible agents such as asbestos, coal, and silica dust lead to chronic inflammation in the lungbecause of the inability of the immune system to remove the substances. Such sterile inflammationsincrease the incidence of epithelial cancers including mesothelioma and lung carcinoma.[32]Experimental evidence that chronic sterile inflammation can cause cancer comes from studies inBALB/c mice that received intraperitoneal administration of nondigestible, nongenotoxic mineral oilsor plastic disks. The mice developed a high incidence of B lymphocytic (plasma cell) tumors but noepithelial cancers.[22]Cigarette smoke is a complex proneoplastic agent that may act, in part, by inducing a chronicinflammatory condition. Smoking not only causes chronic bronchitis, but also delivers an array ofgenotoxic carcinogens (eg, nitrosamines, peroxides) into the lungs. Hence, at present, it is unclear towhat degree chronic bronchitis, mutagens in the smoke, and other factors contribute to the highincidence of lung carcinoma among smokers.There are limitations, however, to using epidemiology to understand the causes of cancer. Definitiveevidence that chronic inflammation predisposes to cancer requires identification of the causativeinflammatory mediators as well as the agents that prevent neoplastic transformation throughinhibition of the inflammatory process. The remainder of this review will focus on the mechanismswhereby inflammatory mediators promote neoplastic transformation.General Mechanisms of Proneoplastic ActivityTumorigenesis is generally a protracted and complex process involving different developmentalstages often referred to as initiation, promotion, and progression.[33] Much of our understanding ofthese steps derives from studies of epidermoid carcinogenesis such as skin and colon cancer.Initiation is thought to involve a primary mutation in the DNA leading to a cell with increasedpotential for growth but still dependent on additional genotypic and phenotypic changes to achievecomplete transformation. Frequently, initiation is induced by genotoxic carcinogens that directlydamage the DNA, while promotion involves clonal expansion of initiated cells. In early skincarcinogenesis studies, promotion was thought to be caused primarily by epigenetic mechanismsthat stimulated expansion of a preneoplastic population of mutated cells.[34] However, it is nowapparent that promotion involves genetic as well as epigenetic changes.[33] Progression is theadvancement of an early neoplastic clone of cells into a fully malignant phenotype via both geneticand epigenetic mechanisms. Malignant cells have minimal requirements for normal growth factorsand are relatively unresponsive to normal growth regulation, resulting in the uncontrolled growththat is the hallmark of cancer.Because tumor cells contain more than one mutation, it may be difficult to know which should beclassified as causing initiation, promotion, or progression, although this distinction may not berelevant. In this review, we will use the terms tumor promoter/promotion in a generic sense; ie, asany proneoplastic activity. Several general mechanisms of proneoplastic activity are recognized andare summarized as follows.MutagenesisThe establishment of a mutation is a sine qua non of cancer: All cancer cells contain permanentchanges to the DNA such that the transformed phenotype is inherited following multiple celldivisions. Under normal conditions, mutation of a critical gene results in a loss of cellularhomeostasis and the ultimate death of the cell. Proneoplastic mutations, on the other hand, confer aselective growth or survival advantage to the cell. As a result, a cell that "should" die manages tosurvive sufficiently to undergo secondary changes, permitting growth under conditions in which anormal cell would either die or be static. Most notable among proneoplastic mutations are those thatresult in increased expression of oncogenes (eg, myc, ras, abl, bcl-2) or decreased activity oftumor-suppressor genes (eg, p53, Rb).[33]Neoplastic alterations of these genes derive from point mutations, deletions, and chromosomaltranslocations. Almost all tumor cells have an affected identifiable oncogene or suppressor gene.Their gene products have diverse mechanisms of action involving different metabolic pathways inthe cell. However, they all commonly confer a selective growth or survival advantage to the cell.Phenotypic changes representative of proneoplastic mutations include a decreased need formetabolites and growth factors, abnormal signal transduction, inappropriate expression of receptorsfor available growth factors (epidermal growth factor receptor, HER2/neu), dysregulation of cell-cyclecheckpoints, and resistance to apoptosis.[33]

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Cell ProliferationIt is widely thought that any agent that causes increased cell proliferation increases the risk ofneoplastic transformation. The rationale for this concept is that DNA synthesis associated with celldivision is necessary to convert a potentially transient change in the DNA into a permanent one. Thatis, for a mutation to occur, the damage to the DNA must survive the many DNA repair processes andmust be readable by DNA polymerase, which creates and locks in the mutation. DNA damage thatblocks DNA synthesis results in cell death, thus eliminating the possibility of a mutation in that cell.In addition, although replicative DNA synthesis is a precise process, errors do occur, and these canlead to the incorporation of a mutation. If, by chance, this mutation results in a selective growth orsurvival advantage to the cell, it may become a precancerous lesion.AdaptationCells have the ability to turn on and off the genes that help them survive toxic signals (eg, inductionof P450 enzymes for metabolism of toxic chemicals and drugs). This adaptation to an adversegrowth environment is usually transient and allows normal cells to survive until the potentially toxiccondition is alleviated. However, under circumstances of prolonged stress, such as during chronicinflammation, a mutation may lock in the growth-advantaged phenotype. Hence, prolongedexposure to stress can result in selection of preneoplastic cells. Some examples of adaptive changesin a cell are increased expression of antioxidant enzymes, matrix metalloproteinases, and growthfactor receptors; increased anaerobic respiration; and de novo synthesis of angiogenic factors.AngiogenesisOne exciting new concept in cancer treatment comes from the understanding that tumorigenesisrequires new blood vessel formation (angiogenesis, neovascularization) in solid tissues. Normaltissues have a fixed blood supply and do not incur angiogenesis unless undergoing developmentalchanges (eg, embryogenesis, menstrual cycle) or recovering from a wound. Tumors, on the otherhand, must develop a new blood supply in order to survive.Studies in experimental tumor models suggest that the inhibition of angiogenesis can impede tumorgrowth and metastasis and can cause preformed tumors to necrose and regress. Chronicinflammation is closely associated with angiogenesis, as granulation tissue requires an extendedvascular supply.[35] Macrophages, platelets, fibroblasts, and tumor cells themselves are a majorsource of angiogenic factors such as basic fibroblast growth factor, vascular endothelial growthfactor, inflammatory cytokines (eg, tumor necrosis factor [TNF]-alpha, interleukin [IL]-1-beta, IL-6,chemokines (eg, IL-8, GRO-alpha), prostaglandins-1 and -2, and nitric oxide.[35]Inhibition of ApoptosisExcept during development and tissue regeneration, normal tissues exhibit a precise balancebetween the rate of cell division and cell death. Disruption of this balance in favor of excess growthsignals possible oncogenesis. Because dead or dying cells are rarely detected in normal tissue, it isthought that normal (programmed) cell death occurs through a controlled process called apoptosis.Apoptotic cells have unique morphologic and biochemical characteristics that distinguish them fromnecrotic cells.[36] The main physiologic difference between apoptosis and necrosis is in how the cellsaffect the surrounding tissues: Cells dying by apoptosis are recognized and taken up by phagocyticcells before they have an opportunity to lyse and release their content into the tissue.[37] Thephagocytes degrade the cells with minimal environmental disturbance and no induction ofinflammation. In contrast, cells dying by necrosis lyse before being taken up by phagocytes,[38]thereby causing an inflammatory response that can cause incidental damage to the surroundingtissue.Treatment with chemotherapeutic drugs or depletion of growth factors usually kills tumor cells byinducing apoptosis,[39] whereas high levels of oxidants, chemicals, or severe hypoxia usually inducenecrotic death. Cells that have become resistant to apoptosis have a greatly increased risk of beingor becoming neoplastic. An appreciation for the strong association between reduced apoptosis andtumorigenesis was advanced by the discovery that the oncogene bcl-2, which mediates B-celltumorigenesis, acts by inhibiting normal B-cell apoptosis.We now know that many different oncogenes act by inhibiting apoptosis, thereby conferring asurvival advantage to preneoplastic and malignant cells. By the same token, normaltumor-suppressor genes such as p53 and Rb promote apoptosis in response to toxic stimuli, inducingappropriate death in a damaged cell.[40] Any agent that prevents cells from dying in response totoxic stimuli can have the effect of promoting tumorigenesis by allowing proliferation of an abnormalcell.Proneoplastic Inflammatory MediatorsInflammatory cells secrete soluble factors that can contribute to the promotion of tumorigenesis

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through all of the above mechanisms. This provides a strong basis for understanding how chronicinflammation can predispose to the development of cancer. The remainder of this review will focuson the role of three different types of inflammatory mediators that have documented ability to serveas tumor promoters: (1) reactive oxygen and nitrogen molecules, (2) cytokines, and (3)prostaglandins. Although these mediators are often studied and discussed in isolation, there issignificant interaction and synergy among them—for example, prostaglandins induce expression ofcertain inflammatory cytokines, which can, in turn, induce production of reactive oxygen andnitrogen species.Reactive Oxygen and Nitrogen IntermediatesWhen phagocytes (neutrophils, eosinophils, monocytes, macrophages) are exposed to aninflammatory stimulus (eg, bacteria), they become activated and begin to generate large quantitiesof reactive oxygen and nitrogen intermediates.[41] Reactive oxygen intermediates, also genericallyreferred to as oxidants, are derivatives of molecular oxygen such as superoxide, hydrogen peroxide,hypochlorous acid, singlet oxygen, and the hydroxyl radical. Under normal circumstances,phagocyte-derived oxidants serve a protective function by killing invading bacteria and parasites.However, they can also have detrimental effects, causing tissue damage and contributing to thedevelopment or progression of numerous diseases including cancer.[41] The same is true forreactive nitrogen intermediates, which are generated by inflammatory phagocytes through theenzymatic synthesis of nitric oxide by an inducible nitric oxide synthase and the subsequentinteraction with molecular oxygen or reactive oxygen intermediates.[42] Proneoplastic Mechanisms—Our best understanding of the proneoplastic activity of reactiveoxygen and nitrogen intermediates comes from their ability to induce damage to DNA.[43,44]Exposure of cells to activated phagocytes leads to oxidative and nitrosative modification of bases,and single-strand breaks.[45-47] Despite the presence of a wide array of mechanisms to repairoxidatively damaged DNA, the repair process is slow and not always complete.[48] Furtherprocessing of damaged DNA leads to proneoplastic mutations, including point mutations, deletions,sister chromatid exchanges, and chromosomal translocations.[49]Proteins[50] and lipids[51] are also significant targets for oxidative attack, and modification of thesemolecules can increase the risk of mutagenesis. For example, oxidative modification of lipids cancause mutagenesis through the formation of genotoxic lipid peroxidation by-products that react withthe DNA.[44,52] Protein oxidation may indirectly promote mutagenesis through oxidativemodification of DNA polymerase or inhibition of DNA repair enzymes. Agents that either scavengereactive oxygen and nitrogen intermediates or prevent their formation inhibit induction of DNAdamage, mutagenesis, and transformation by inflammatory phagocytes. This forms the basis for thetheory that dietary antioxidants can inhibit the development or progression of cancer.This review focuses on the DNA-damaging effects of reactive oxygen and nitrogen intermediates, butother proneoplastic mechanisms may also be important. For example, chronic exposure to low levelsof reactive oxygen intermediates stimulates signal transduction and cell proliferation. In addition,subtoxic levels of reactive oxygen intermediates induce activation of genes that support escape fromnormal growth controls, including induction of genes that code for antioxidant enzymes such ascatalase and superoxide dismutase. Overexpression of these proteins can result in adaptation andsurvival in the face of high levels of oxidants that should be cytotoxic.[53] These mechanisms mayplay an important role in oxidant-mediated tumorigenesis and have been reviewed elsewhere.[52]Superoxide, Hydrogen Peroxide, and the Hydroxyl Radical—Reactive oxygen and nitrogenintermediates have varying degrees of reactivity and diffusability that influence their mutagenicpotential.[43] Superoxide is the primary product of the phagocytic oxidative burst and is generatedby a membrane-associated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.[41]Superoxide is not particularly reactive with biomolecules and cannot diffuse across cell membranes.It rapidly dismutates—either spontaneously or catalytically through the action of superoxidedismutase—to hydrogen peroxide, which also is not particularly reactive on its own. However,hydrogen peroxide can diffuse significant distances and cross cell membranes like water.The biological danger from superoxide and hydrogen peroxide comes when there is a redox-activetransition metal present, such as iron (Fe) or copper (Cu). Interaction of Fe2+ or Cu1+ with hydrogenperoxide generates highly reactive radicals such as the hydroxyl or ferryl radicals. Superoxide servesas a source of hydrogen peroxide and acts also to maintain the transition metals in the reducedstate, thus supporting radical formation. The hydroxyl radical is too reactive to diffuse any significantdistance and will react with the first molecule with which it comes in contact. Hence, the site wherethe hydroxyl radical is formed is also the site of its damage.DNA contains a significant amount of bound iron and copper. When phagocyte-derived hydrogen

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peroxide diffuses into the nucleus of the target cell, it interacts with the transition metal on the DNA,forming a radical and giving rise to strand breaks and base modifications.Peroxynitrite—In addition to its pivotal role in supporting the formation of the hydroxyl radical,superoxide has the additional effect of reacting with nitric oxide to generate peroxynitrite.[42] Unlikenitric oxide and superoxide, which have limited reactivity with biomolecules, peroxynitrite and itshydrogenated counterpart peroxynitrous acid react with most biomolecules yet have a significantdiffusion distance as well—a potent combination. Peroxynitrite generated outside of the cell cancause damage to the DNA inside the nucleus. In this regard, the formation of peroxynitrite may beone of the most dangerous products of activated phagocytes. Note that in order for peroxynitrite tobe formed, both NADPH oxidase and nitric oxide synthase must simultaneously be active in the cell.Reactive nitrogen intermediates can induce DNA damage and mutations via several differentmechanisms.[42] Like the hydroxyl radical, peroxynitrite has the ability to bring about DNA basemodifications, strand breaks, and mutations through oxidative mechanisms. In addition, the productsof nitric oxide synthesis have a second important pathway for inducing mutations that comes fromthe formation of nitrosamines through N-nitrosation of secondary amines. N-nitrosamines are highlymutagenic and carcinogenic and, hence, may be particularly important mediators of carcinogenesisinduced during chronic inflammation.[47]Hypochlorous Acid—In addition to synthesizing superoxide and nitric oxide, activated neutrophils,monocytes, and eosinophils generate large quantities of hypochlorous acid, the active ingredient inhousehold bleach. The formation of hypochlorous acid from hydrogen peroxide and chloride iscatalyzed by myeloperoxidase, which comprises approximately 5% of the total protein ofneutrophils, or by the homologous eosinophil peroxidase. Hypochlorous acid is a strong oxidant thatalso has the ability to diffuse across cell membranes, and although it is not thought to cause DNAstrand breaks, it can cause DNA base modifications leading to mutations.Lines of Evidence—Support for the theory that phagocyte-derived oxidants contribute tomutagenesis and carcinogenesis comes from several lines of evidence.(1) Inflammatory phagocytes have the capacity to induce oxidative and nitrosative DNA damage andmutagenesis in neighboring cells. Thus, co-incubation of cells with activated neutrophils ormacrophages fosters the induction of strand breaks and oxidative base damage. The most commonmutations induced by reactive oxygen and nitrogen intermediates are base modifications leading topoint mutations. Prominent among these is 8-oxo-2-deoxyguanosine (8-oxodG), which is misread byDNA polymerase to generate GC-to-TA transversions.[43] In addition, oxidants cause the formationof gross chromosomal abnormalities such as sister chromatid exchanges, deletions, andinversions.[54](2) Incubation with activated neutrophils or macrophages results in neoplastic transformation offibroblasts and epithelial cells.[55,56] The induction of chromosomal damage and neoplastictransformation by activated phagocytes can be inhibited with antioxidant compounds, indicating thatoxidants are mediators of phagocyte-mediated cell transformation.[54,55](3) The types of mutations found in some tumor cells are reflective of oxidative damage. Forexample, the GC-to-TA transversions that are induced by reactive oxygen and nitrogenintermediates are commonly found in Ras codons 12, 13, and 61, leading to activation of theoncogene, and in "hot spots" in the tumor-suppressor genes p53 and Rb.(4) Tumor promoters such as PMA and benzoyl peroxide are known for their ability to activate theoxidative burst of neutrophils and macrophages, and PMA causes oxidative base damage in theskin.[57] This represents a possible common mechanism of tumor promotion by these agents.Compounds that inhibit tumor promotion in the mouse skin cancer model also inhibit the respiratoryburst of phagocytes.(5) Chronic inflammation is accompanied by increased production of tissue reactive oxygen andnitrogen intermediates. Evidence of this process is documented in studies of the markers ofoxidative activity in vivo. Thus, oxidatively and nitrosatively modified DNA and proteins are presentin chronically inflamed tissue or the body fluids of patients with chronic inflammatory conditions. Thelikely source of the oxidative activity is the polymorphonuclear neutrophils and macrophagesrecruited as part of the inflammatory response. Markers of oxidative damage are also elevated intumor tissues,[58] but it is unclear whether these are caused by oxidants generated byinflammation-associated leukocytes or whether the damaging oxidants come from the tumor cellsthemselves.[59]In addition, the inducible form of nitric oxide synthase, thought to be responsible for the generationof nitric oxide in inflamed tissues, is up-regulated in chronically inflamed tissues, including gastrictissue associated with H pylori infection.[47] While increased expression of inducible nitric oxide

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synthase is seen in inflammatory bowel disease, it is unclear whether it actually promotes orattenuates the inflammatory condition, because knockout mice display an increased susceptibilityfor colitis.[60]Overall, although there is some disagreement as to whether phagocyte-derived oxidants contributeto tumorigenesis,[61] there is a significant body of experimental data supporting the conclusion thatthey do.ProstaglandinsEvidence from human and animal studies suggests that prostaglandins contribute to thedevelopment of cancer.[62,63] Prostaglandins such as prostaglandin E2 (PGE2) are lipid mediators ofthe inflammatory immune response and are derived from oxidative metabolism of arachidonic acid.These lipids are synthesized in large quantities by inflammatory cells in response to both acute andchronic inflammatory stimuli.Two different cyclooxygenase (COX) enzymes catalyze the rate-limiting first step in prostaglandinsynthesis.[64] COX-2 is expressed during inflammation. Its primary site of synthesis is inflammatorymonocytes and macrophages, but it is also expressed in noninflammatory cells such as fibroblasts,epithelial cells, and endothelial cells. In vitro expression of COX-2 is induced by bacterial cellproducts and inflammatory cytokines. Notably, prostaglandin synthesis can also be stimulated byperoxynitrite,[65] thereby providing for synergy between these two procarcinogenic inflammatorymediators. Experimental induction of COX-2 in animal models is accomplished with agents thatinduce chronic inflammation such as administration of azoxymethane to rats. COX-1 is a constitutiveenzyme expressed in most cell types and is associated with regulation of housekeeping functionssuch as gastric acid secretion. Lines of Evidence—Two significant findings represent strong evidence that prostaglandinsmediate human inflammation-associated carcinogenesis. First, the incidence and progression ofcolon cancer is diminished by long-term intake of nonsteroidal anti-inflammatory drugs (NSAIDs)such as aspirin or sulindac.[62,66,67] These drugs share the ability to inhibit cyclooxygenase activityand prostaglandin synthesis. Although this may not be their only mechanism for inhibiting tumordevelopment,[62] it is a likely mechanism because other activities of NSAIDs, such as inhibition ofangiogenesis,[68] require high drug concentrations that are unlikely to be achieved at therapeuticdoses in humans.Second, COX-2 is elevated in inflammatory bowel diseases and is associated with an increased riskof colon carcinogenesis. The endogenous agents responsible for inducing COX-2 expression in theinflamed colonic mucosa are unknown as yet. COX-2 is also overexpressed in 85% ofadenocarcinomas, suggesting that there is a link between COX-2 activity and tumor growth. Thelikely cellular sources of prostaglandins in tumor tissue are the inflammatory monocytic cells thatinfiltrate the colonic mucosa. PGE2 is also elevated in the tumor tissue and blood of patients withcolon cancer. If these prostaglandins promote tumor growth, then NSAIDs may not only preventcolon carcinogenesis but may also provide a means of limiting tumor progression.[63]Animal Models—Important evidence that prostaglandins promote carcinogenesis also comes fromanimal models showing that experimentally induced tumor formation or progression can be inhibitedby NSAIDs. In a murine model of colon carcinogenesis associated with familial adenomatouspolyposis, it was demonstrated that knockout of the COX-2 gene or administration of a selectiveCOX-2 inhibitor reduced the incidence of colon carcinogenesis.[69] Similarly, inhibition of chemicallyinduced colon carcinogenesis by COX-2 inhibitors has been demonstrated in a rat model.Animal models suggest that other inflammation-associated cancers may also be promoted byprostaglandins. For example, pristane-induced plasma cell tumorigenesis in BALB/c mice is inhibitedby the administration of indomethacin in the drinking water.[22] Injection of pristane into theperitoneal cavities of BALB/c mice induces a chronic inflammatory condition associated with amassive influx of neutrophils and macrophages.COX-2 expression is elevated in macrophages, and this is associated with elevated peritoneal PGE2

levels.[70] Treatment of mice with indomethacin significantly inhibits tumor development and, asexpected, completely inhibits PGE2 production by the inflammatory macrophages.[71] The levels ofindomethacin achieved in the peritoneal cavity are low (µm range) and are unlikely to inhibitenzymes other than the cyclooxygenases (E. Shacter, J. Wax, and M. Potter, unpublished results,1992).Skin carcinogenesis in experimental mouse models also involves PGE2, and here, too, NSAIDs arepreventive. Similarly, progression of mouse mammary tumorigenesis is inhibited by administration ofNSAIDs.[72] Mammary tumors are often infiltrated with inflammatory macrophages, which, togetherwith the tumor cells themselves, are potent sources of endogenous PGE2.

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Mechanisms of Tumorigenesis—Many different mechanisms have been proposed to explain howprostaglandins promote tumorigenesis.[63] These mechanisms are briefly described below.(1) Prostaglandins can stimulate cell proliferation.(2) PGE2 induces synthesis of cytokines such as IL-6 that serve as tumor growth factors.(3) Synthesis of prostaglandins is coupled with formation of DNA-reactive by-products withmutagenic potential; eg, formation of malondialdehyde from prostaglandin G2.(4) COX enzymes can catalyze the oxidative metabolism of xenobiotics, leading to the formation ofgenotoxic mutagens.(5) Prostaglandins can induce angiogenesis, which is required for growth and metastasis of tumors.Some evidence of this comes from the demonstration that NSAIDs inhibit angiogenesis in vitro. It hasbeen suggested that these drugs may not be acting entirely through the inhibition of PGE2 synthesisbecause the addition of exogenous PGE2 fails to overcome the inhibitory effect of the NSAIDs.[68]However, the concentrations of NSAIDs required to inhibit prostaglandin-independent angiogenesisin vitro are quite high (eg, 250 to 500 µM of indomethacin) and are unlikely to be achieved in vivo. Incontrast, inhibition of prostaglandin synthesis by NSAIDs occurs at concentrations that are achievedin vivo (eg, 1 µM or less for indomethacin).[73](6) In addition to serving as proinflammatory mediators, prostaglandins are also immunosuppressive.By inhibiting the functions of T cells and macrophages, they may decrease immune surveillance andthereby allow nascent tumor cells to escape detection by the immune system.(7) Prostaglandins may inhibit apoptosis of tumor cells by increasing expression of the antiapoptoticoncogene bcl-2 or by removing arachidonic acid, which is thought to be proapoptotic.(8) Prostaglandins can stimulate cell signaling through peroxisome-proliferator-activated receptordelta, a transcription factor that regulates proliferation-associated genes.CytokinesInflammatory cells secrete a large number of cytokines and chemokines that can promote theoutgrowth of neoplastic cells. These factors are produced in response to proinflammatory stimulisuch as bacterial lipopolysaccharide. Neoplastic cells have a reduced need for normal metabolicfactors, but they often require the presence of specific cytokines in order to proliferate, at least inthe early stages of tumor development. Many tumor cells developing in chronically inflamed tissuecultivate a growth advantage by acquiring the ability to proliferate in response to cytokines. Theymay express growth factor receptors abnormally or alter their response to the factors by undergoingcell division instead of differentiation.Examples of tumor cell cytokine dependence in human disease are the growth dependence of AIDS-and EBV-associated B-cell lymphomas, B-cell leukemias, and multiple myeloma on the inflammatorycytokines IL-6[74] and IL-15,[75] and the dependence of malignant mesothelioma on platelet-derivedgrowth factor. Monocytes, macrophages, and T cells are major sources of cytokines that promoteoutgrowth of preneoplastic and malignant cells, in addition to autocrine growth factor production bythe tumor cells themselves. Tumor-Progression Mechanisms—Cytokines can contribute to tumor progression by mechanismsother than direct stimulation of cell growth. One such mechanism involves inducing the production ofreactive oxygen and nitrogen intermediates. For example, TNF-alpha is known to enhance theformation of reactive oxygen intermediates by neutrophils and other cells. IL-1-beta, TNF-alpha, andinterferon (IFN)-gamma stimulate expression of inducible nitric oxide synthase and the formation ofnitric oxide in cholangiocarcinoma. This process has been shown to cause DNA damage and inhibitDNA repair in tumor cells.IL-8 can promote tumorigenesis through two different mechanisms. One involves induction ofangiogenesis, possibly through the synthesis of matrix metalloproteinases. In addition, IL-8 recruitsinflammatory neutrophils to the site of inflammation and may thereby increase formation of reactiveoxygen and nitrogen intermediates. Some cytokines may also promote tumorigenesis by inducingimmunosuppression, as is suggested for transforming growth factor-beta. Animal Models—Several animal models have demonstrated the role of inflammatory cytokines intumorigenesis associated with chronic inflammation. Pristane-induced plasma cell tumors in micerequire IL-6 for their growth; macrophages in the chronically inflamed tissue provide the IL-6.Production of IL-6 in this system is stimulated by PGE2 and inhibited by the administration ofindomethacin.[70,71] As noted above, the PGE2 is probably derived from COX-2, which is elevated ininflammatory macrophages from pristane-treated mice. Knockout of the IL-6 gene inhibitsexperimental plasmacytomagenesis.[76]A second experimental system for elucidating the role of inflammatory cytokines in tumorigenesis isseen with TNF-alpha, which is induced by tumor promoters in experimental skin carcinogenesis

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models. Knockout of the TNF-alpha gene in mice significantly inhibits the development of skin tumorsin response to DMBA and phorbol esters.[77] IL-8, an inflammatory CXC chemokine derived frommonocytes, macrophages, and endothelial cells, is implicated in the progression and metastasis oftumors in the colon, bladder, lung, and stomach.Treatment and PreventionMany of the inflammatory mediators described in this review promote both the initiation andprogression of cancer. As such, it should be possible to devise strategies to slow or preventtumorigenesis and tumor progression.NSAIDs and Novel AgentsChronic intake of NSAIDs may reduce carcinogenesis by inhibiting production of prostaglandins,cytokines, and angiogenic factors. Note that NSAIDs do not eliminate inflammation but rather act byreducing the production of selected inflammatory factors. Hence, unlike steroids, they do notsuppress elements of the immune response that are necessary for tumor depletion such as T cells,NK cells, and macrophages. COX-2 selective inhibitors may provide a safer method forchemoprevention than older NSAIDs such as aspirin and indomethacin, which also inhibit COX-1activity and cause gastric lesions.Potential therapies for tumors that depend on inflammatory cytokines for growth or metastasis mayderive from modalities that either remove the cytokines (eg, monoclonal antibodies or solublereceptors), block cytokine receptors, or target toxins to tumor cells bearing high levels of growthfactor receptors. All these approaches are currently being explored in clinical trials.Dietary AntioxidantsEating a diet rich in fruits and vegetables is thought to be the best and safest means of preventingcancer. Epidemiologic studies suggest that diets high in fruits and vegetables are strongly associatedwith a lower incidence of different forms of cancer. This approach to cancer prevention has beenreviewed elsewhere.[78]Because fruits and vegetables contain high levels of antioxidant compounds (eg, carotenoids,polyphenols, vitamin C), and because oxidants have a known capacity to promote neoplastictransformation, it has been postulated that consumption of antioxidant supplements may preventsome forms of cancer. More definitive evidence that reactive oxygen and nitrogen intermediatesderived from inflammatory phagocytes can lead to tumorigenesis will depend on the completion ofan intervention trial demonstrating that interference with radical formation or activity reduces tumordevelopment or progression.The Food and Nutrition Board of the Institute of Medicine recently examined the role of oxidants indisease in order to determine whether dietary antioxidants inhibit the development of chronicdiseases such as atherosclerosis and cancer (see http://books.nap.edu/books/0309061873/html/index.html). The panel of experts concluded that, atpresent, there are insufficient human data to conclude that dietary antioxidants, such as vitamins Cand E, carotenoids, and selenium, can prevent cancer. The lack of supportive evidence is due, inpart, to the complexities of designing and conducting a suitable intervention trial and to thelong-term nature of tumor development. Trials that are of short duration or that are conducted inolder individuals may only be looking at tumor progression and not initiation events.If oxidants are involved primarily in initiation through the induction of DNA damage, and this occursyears (or decades) before tumor outgrowth begins, then administration of antioxidants over a narrowwindow of time later in life would likely be ineffective. Studies of NSAID inhibition of colon cancerindicate that the drugs must be taken for many years in order to lower tumor incidence. The samemay hold true for antioxidant supplements.Antioxidants Plus ChemotherapyIn addition to inhibiting de novo carcinogenesis, antioxidants may improve cancer treatment byenhancing antineoplastic therapy. Solid tumors are often infiltrated with inflammatory phagocytes,and tumor tissues can contain higher than normal levels of reactive oxygen intermediates.[58,79] Ithas recently been discovered that oxidants can interfere with the induction of apoptosis bychemotherapeutic agents (eg, etoposide, doxorubicin, fluorouracil) and that these effects can beovercome with antioxidant compounds.[38,80] Hence, the oxidative stress associated withinflammation in tumor tissue may interfere with cancer treatment.The experimental findings are relevant in light of the fact that oncologists generally advise theirpatients not to take antioxidant supplements while receiving chemotherapy. The basis for thisrecommendation comes from the theory that most chemotherapeutic drugs act by generatingintracellular oxidants to kill the target tumor cells, mostly by inducing apoptosis. Thus, any agentthat interferes with the pro-oxidant activity of the drugs might interfere with efficacy.

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http://books.nap.edu/books/0309061873/html/index.html


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