Inflammation, carcinogenesis and cancer

International Immunopharmacology 1 Ž2001. 1651–1667 www.elsevier.comrlocaterintimp

Review

Inflammation, carcinogenesis and cancer F.A. Fitzpatrick Huntsman Cancer Institute, 2000 Circle of Hope, UniÕersity of Utah, Salt Lake City, UT 84112-5550, USA Received 9 May 2001; accepted 17 May 2001

Abstract To fulfill their role in host-defense, granulocytes secrete chemically reactive oxidants, radicals, and electrophilic mediators. While this is an effective way to eradicate pathogenic microbes or parasites, it inevitably exposes epithelium and connective tissue to certain endogenous genotoxic agents. In ordinary circumstances, cells have adequate mechanisms to reduce the genotoxic burden imposed by these agents to a negligible level. However, inflammation persisting for a decade eventually elevates the risk of cancer sufficiently that it is discernible in case control epidemiological studies. Advances in our understanding of tumor suppressors and inflammatory mediators offer an opportunity to assess the molecular and cellular models used to guide laboratory investigations of this phenomenon. Disappointing results from recent clinical trials with anti-oxidant interventions raise questions about the risks from specific endogenous agents such as hydrogen peroxide and oxy radicals. Simultaneously, the results from the anti-oxidant trials draw attention to an alternate hypothesis, favoring epigenetic inactivation of key tumor suppressors, such as p53, and the consequent liability this places on genomic integrity. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Inflammation; Carcinogenesis; Cancer

1. Introduction It is timely to review the association between persistent inflammation, carcinogenesis and cancer. Section 2 discusses the epidemiological data supporting such an association. Section 3 depicts a conventional molecular and cellular model for the increased

AbbreÕiations: COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug; PG, prostaglandin E-mail address: [email protected] ŽF.A. Fitzpatrick..

risk of cancer, secondary to persistent inflammation. Section 3 also discusses the utility and limitations of this current model. For prominent electrophilic mediators of inflammation Žhydrogen peroxide and oxy radicals, nitric oxide, malondialdehyde, 4-hydroxynonenal, and eicosanoids., previously overlooked epigenetic mechanisms may contribute greatly to the disruption of genomic integrity. Section 4 discusses the role of cyclooxygenase ŽCOX. isoenzymes in cancer, distinct from their role in inflammation. Section 4 also discusses the benefits and limitations of non-steroidal anti-inflammatory drugs ŽNSAIDs. in cancer prevention, and the case for assessing alternative anti-inflammatory agents for their benefitsrrisks in cancer prevention.

1567-5769r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 7 - 5 7 6 9 Ž 0 1 . 0 0 1 0 2 - 3

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2. Persistent inflammation and cancer risk: epidemiological evidence 2.1. UlceratiÕe colitis and colon cancer Inflammation, occurring episodically but persistently over a decade, is a risk factor for several types of cancer ŽTable 1.. Ulcerative colitis typifies this premise w1–7x. In a large study, involving over 3000 patients with chronic ulcerative colitis, investigators observed an incidence of colon cancer 5.7-fold higher than expected w2x. This increased risk of cancer correlated with Ži. the severity of disease, ranging from 1.7-fold for patients with ulcerative proctitis to 14.8-fold for patients with total colonic inflammation Žpancolitis.; and Žii. the duration of the disease. Colitis persisting for 35–40 years carries an absolute risk of colon cancer ranging from 30% to 40% w2,4x. Additionally, colon cancer associated with ulcerative colitis has the worst prognosis and lowest 5-year survival rate Ž- 40%., among three high-risk groups, including familial adenomatous polyposis, and hereditary non-polyposis colorectal cancer w6x. Importantly, ulcerative colitis does not increase the risk of other types of cancer w7x, consistent with the hypothesis that neoplasia results in part from persistent, local inflammation ŽFig. 1.. Microsatellite instability occurs in the mucosa of 50% of patients who have no dysplasia, suggesting that cumulative disruption of genomic integrity accompanies inflammation and precedes transformation w8x.

Management of colitis with the anti-inflammatory agent sulfasalazine can reduce the incidence of colon cancer w9,10x. The anti-inflammatory mechanism Žsic. of sulfasalazine is either uncertain, non-specific, pleiotropic or all three depending on one’s preference. As expected in an inflammatory environment, COX-2 is highly expressed in ulcerative colitis w11,12x. However, selective COX-2 inhibitors exert little or no anti-inflammatory effect in animal models of inflammatory bowel disease. It is debatable whether they will confer any anti-neoplastic benefit in humans w12–14x based on their suppression of colitis. 2.2. Lung inflammation and lung cancer Localized, chronic inflammatory disorders appear to increase the risk for cancer in several other organs, including the lung, pancreas, esophagus, and skin. Analysis of cancer incidence in asthmatic patients in five separate epidemiological studies is intriguing. A case-control study, involving 78,000 patients with asthma, showed significant excess risk of lung cancer in both men and women, consistent with a contribution from local, chronic inflammation w15x. A second study on 31,000 patients reported a significantly increased risk of death from lung cancer in men with asthma, after adjustment for cigarette smoking habits Žhazard ratio 3.19. w16x. A third study on 64,000 patients with asthma reported a reduced risk of most cancer types with the exception of lung

Table 1 Association of inflammation with cancer Inflammatory condition

Oncogenic consequences

References

Ulcerative colitis) 8 years Asthma

≠ Risk of colon cancer ≠ Risk of lung cancer x Risk of several cancers, except lung cancer ≠ x Uncertain association with risk of ovarian cancer ≠ Risk of ovarian cancer ≠ Risk of bladder cancer ≠ Risk of pancreatic cancer Association with penile cancer ≠ Risk of dysplasia ≠ Risk of lung, liver, skin cancer ≠ Risk of verrucous carcinoma

w1–10x w15–19x

Pelvic inflammatory disease Ovarian epithelial inflammation Eosinophilic cystitis Pancreatitis Foreskin inflammation and phimosis Barret’s esophagous Sarcoidosis Ulcerative lichen planus Žinflammatory mucocutaneous disorder.

w36,37x w31–33,35x w26,27x w38–41,43x w28x w44,45x w25x w29,30x

F.A. Fitzpatrickr International Immunopharmacology 1 (2001) 1651–1667

Fig. 1. Localized inflammation correlates with risk for localized cancer. Ulcerative colitis.

cancer and endocrine cancer w17x, suggesting that asthma confers a protective effect on certain organs, but not the respiratory tract. Finally, two population based, case-control studies involving lifetime nonsmoking women participants both affirmed that asthma elevates the risk for lung cancer w18,19x. Can one reconcile a AprotectiveB effect of asthma against cancer in certain organs with its detrimental effect on the lung? Yes, if one accepts that asthmatics abstain or smoke infrequently w20x. In this context, the elevated risk of lung cancer observed in asthmatic patients is even more striking. Local inflammation then becomes one plausible source of the heightened risk of lung cancer, considering that asthmatic patients often endured persistent lung inflammation prior to the introduction of treatment guidelines recognizing asthma as an inflammatory disorder of the airway w21–23x. It is important to acknowledge an alternative hypothesis that inhaled corticoids used in asthma management might create a localized immune deficiency in the lung, and this local immune deficiency increases the risk of cancer. However, this latter hypothesis is not fully consistent with models of particle-induced lung cancer which favor inflammation as an endogenous source of mutations w24x. 2.3. Inflammation and cancers of the oÕary, pancreas, bladder, skin and esophagus Other representative associations between inflammation, carcinogenesis, and cancer include lung and

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liver cancer following sarcoidosis w25x; bladder cancer in humans with eosinophilic or irritant-induced cystitis w26,27x, skin cancer w28x, verrucous carcinoma w29,30x ovarian cancer w31–36x and Barret’s esophagus w44,45x. The relationship between the number of lifetime ovarian cycles and the risk for ovarian cancer is partly endocrinological, but the granulocytic inflammation that accompanies ovulation may also contribute w31,32x. The number of ovarian cycles correlates quantitatively with expression of a mutated p53 tumor suppressor in ovarian cancer w33x and it is notable that patients with chronic endometriosis w34x or pelvic inflammatory disease may also have a significantly elevated risk of ovarian cancer w36x. The latter association is debatable since larger case control studies fail to confirm any association between pelvic inflammation and ovarian cancer w37x. Case-controlled studies indicate that chronic pancreatitis is a risk factor for pancreatic cancer w38–40x and mutated alleles of p53 occur in resected, morphologically normal tissue from 10% of patients with chronic pancreatitis w41x, consistent with the molecular genetics of pancreatic cancer progression w42x. However, one population-based study suggests that the risk of pancreatic cancer for patients with chronic pancreatitis declines with time, in contrast to associations between inflammation and cancer in other organ systems w43x. The difficulty of early detection, the rapid course, and the high morbidity of this oncological disorder complicate epidemiological experiments seeking a relationship between pancreatitis and pancreatic cancer. 2.4. Effect of non-steroidal anti-inflammatory drugs on cancer risk With rare exception w49x, over 20 separate investigations during the past 12 years affirm that regular consumption of aspirin or NSAIDs lowers the incidence, or mortality, of colon cancer w50–76x. However, one should interpret these results prudently. The results do support the notion that cyclooxygenase enzyme, a source of eicosanoid mediators, is a participant in the molecular progression of colon cancer w77–82x. However, NSAIDs are not front line therapy for patients with inflammatory bowel disease. In fact, some investigations suggest that their

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use is contra-indicated because they aggravate inflammatory bowel disease w14,83x; other investigations are inconclusive w84x. Thus, the beneficial effects of NSAIDs in colon cancer do not pertain directly to the risk associated with or due to persistent colitis. We discuss the benefits of NSAIDs and the association between cyclooxygenase and cancer in more detail in Section 4 of this review.

3. Molecular and cellular determinants of inflammation-associated cancer 3.1. The conÕentional model The epidemiological data in Section 2 strongly support the conclusion that persistent inflammation raises the risk of cancer within the involved organ, but not distal organs. How does this happen? As part of their normal host-defense function, granulocytes secrete chemically reactive radicals and electrophilic mediators ŽFig. 2.. Thus, inflammation inevitably exposes proximal epithelial and stromal cells to substances with mutagenic potential in vitro w85–89x. Note that activated neutrophils can transform cell lines to variants with neoplastic traits w87,89x. Granulocytes and lymphocytes generate at least four separate types of products that are genotoxic or mutagenic: Ži. hydrogen peroxide and oxy radicals w90–100x; Žii. nitric oxide w101–109x; Žiii. malondialdehyde w110–118x; and Živ. 4-hydroxy-2nonenal w119–122x. The latter two are prominent by-products of lipid peroxidation w123x. Oxy radicals derived from H 2 O 2 can act directly, causing DNA

strand breaks that introduce oncogenic mutations w123,124x, or indirectly by modulating gene transcription w125,126x, and suppressing genomic repair pathways w127,128x. Table 2 summarizes an appreciable collection of data suggesting that oxygen and nitrogen radicals, acting as endogenous mutagens, account for some of the elevated risk of cancer associated with persistent inflammation. In view of this abundant evidence, it might surprise readers to learn that the radical scavenging anti-oxidant, bcarotene, does not reduce the risk of cancer in apparently healthy subjects w129–133x. In high risk populations, it may actually have increased the risk w132x. Physicians’ Health Study II is currently testing vitamin E, in combination with vitamin A and vitamin C, as anti-oxidants w134x. Nevertheless, the failure of b-carotene to confer any benefit in several large, prospective clinical trials should prompt debate about the underlying hypothesis, as well as the trial design. Accordingly, Collins w129x has provided a thoughtful critique of the hypothesis that oxidative DNA damage is a significant risk factor for cancer. His analysis of the literature shows that steady-state estimates of 8-oxo-deoxyguanosine Ž8-oxo-dG. in DNA have declined steadily as analytical methodologies improved. Current levels of 8-oxo-dG composition are sufficiently small to suggest that constitutive antioxidant defenses Žreduced glutathione, catalase, superoxide dismutase, GSH peroxidase. and DNA repair processes can minimize the risk of cancer from endogenous oxidants. If so, what molecules other than oxy radicals might account for the elevated risk of cancer during inflammation? How might they create risks?

Fig. 2. Model for the cellular and molecular basis of inflammation-related cancer risk.

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Table 2 Events associated with disruption of genomic integrity

H 2 O2 Ø Nitric oxide ŽNO . malondialdehyde 4-OH-2-nonenal Eicosanoids

Modification of nucleosides and nucleotides

Modification or damage of DNA

w91,95x

w91–95x w101–106x w112,113x w120,121x w136x

w110,111x w119,120x w135x

Collins suggests that alkylation of DNA poses a more serious risk to genomic integrity than does 8-oxo-dG. In this context, malondialdehyde, 4-hydroxy-nonenal and certain electrophilic eicsoanoids warrant attention. We propose that these agents increase cancer risks from two complementary processes: Ži. direct reaction with nucleophiles on DNA; and Žii. impairment of genomic sentinels, typified by the p53 transcription factor. So far, investigators have neglected the latter process as a risk. 3.2. Epigenetic inactiÕation of tumor suppressor p53: sentinel of genomic integrity Investigations on chemical carcinogenesis often proceed via the following experimental sequence. First, one demonstrates that a chemical reaction between a mutagen and DNA can occur under favorable conditions in vitro. Then one develops ultra-sensitive analysis methods for determining if it does occur in vitro or in vivo. Next, one applies these methods to determine if any occurrence in vivo has oncological significance. This approach is systematic and well-aligned with the hypothesis that loss of genomic integrity causes cancer in a two phase process involving induction and promotion w139x. However, in practice, it focuses primarily on direct chemical modification of DNA as the problem and it neglects epigenetic mechanisms. Furthermore, it positions the investigation of pathological significance at the end of the process. It is possible to consider epigenetic, as well as genetic processes, and to place the pathological significance at the beginning of the investigation by adapting a different approach. This approach relies on the premise that any endogenous agents that disrupt genomic integrity should activate

p53 alteration

w108,109x

w137x

Mutation or transformation of cells w96–100x w101,102,107x w114–118x w122x w138x

a response by the p53 tumor suppressor. Results with this approach have been informative and surprising w108,137x. Cells harboring a wild-type p53 tumor suppressor gene normally maintain a low steady-state concentration of the p53 protein via its post-translational regulation w140–145x. When genomic damage occurs, cells slow their degradation of p53, and accumulate it as a nuclear homo-tetramer to transactivate genes that arrest the cell cycle Žp21WA F1rCIP1 .; repair DNA damage ŽGADD 45.; autoregulate its degradation ŽMDM-2.; or propagate apoptosis ŽBAX.. These responses enable p53 to function as a genomic sentinel w146–149x. Impairment of the p53 gene or protein has grave cellular and medical consequences w150–153x. This impairment can occur by two prominent mechanisms: Ži. mutation or loss of a p53 allele w154–156x; Žii. binding of ubiquitin ligase oncoproteins Že.g. mdm-2, E6. to p53 w157–161x. Estimates suggest that 40–60% of tumors harbor an allelic variant of p53. The vast collection of p53 nucleotide polymorphisms collapses into two classes of mutant p53 proteins. AContactB mutants Žclass I. retain a wildtype conformation but they have altered residues in direct contact with DNA Žamino acid residues 112– 141, 236–251 and 271–286.. AConformationalB mutants Žclass II. have alterations in residues that maintain p53 conformational integrity Žamino acid residues 163–195.. AContactB and AconformationalB mutations each disrupt the p53:mdm-2 auto-regulatory cycle, allowing cells to accumulate appreciable levels of mutant p53 protein Žp53 mut . under basal condition w153,159x. A high basal level of p53 mut and a failure to accumulate more p53 mut in response to genomic damage are distinctive traits of cells harbor-

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ing a mutant p53 gene. In such cells the basal degradation rate of p53 mut is much slower than normal ŽFig. 3.. In certain tumors, viral oncoproteins Že.g. human papilloma virus E6. or mdm-2 impair p53 by binding directly to it; facilitating its conjugation with ubiquitin, and hastening its degradation by the 26S proteasome w144,145x. Very low basal levels of p53 and failure to accumulate p53 in response to genomic damage are distinctive traits of cells harboring oncoproteins with ubiquitin ligase activity. In such cells, the basal degradation rate of p53 is much faster than normal ŽFig. 3.. Distinct from somatic mutation or sequestration by ubiquitin ligases, p53 is redox sensitive. Oxidizing agents Ždiamide, pyrrolidine dithiocarbamate, Ø H 2 O 2 . and nitric oxide ŽNO . donors ŽSNAP or NAP. disrupt the conformation and sequence-specific DNA binding of isolated p53 w108,162,164x. Notably, this requires an appreciable excess of oxidizing agent over isolated p53 w108,162,164x and the redox sensitivities of isolated p53 versus cellular p53 do not always correlate well w165x. Some investigators report that H 2 O 2 impairs DNA binding and transcription by both isolated and cellular p53 w164x; others report that H 2 O 2 activates cellular p53 transcription w166x and nuclear translocation w167,168x. Recently, Wu and Momand w168x and we w137x established that intact cells exposed to 25 m M dithiocarbamate; or to 20 m M prostaglandin ŽPG. A 1 and

PGA 2 accumulate p53 protein that is conformationally, and functionally deranged. These results suggest that distinctive conditions, separable from somatic mutation or association with ubiquitin ligases, can impair cellular p53 ŽFig. 4.. We stress that our model should also apply to other electrophiles. For example, paradoxical effects of benzo w g xchrysene 11,12-dihydrodiol 13,14 epoxide on p53 and p21 expression in MCF-7 cells fit into the framework we propose w163x. Thus, exposure of cells to various endogenous or xenobiotic electrophiles may inactivate p53 by a mechanism analogous to the one described here. Sporadic, or episodic, impairment of p53 via redox or alkylating agents might favor the emergence of cells with a mutator phenotype w169,170x, inaugurating carcinogenesis. This integrated hypothesis offers a framework to investigate why persistent inflammation increases the risk for cancer localized to the site of inflammation. Inflammation bathes epithelial and mesenchymal tissue with exudate containing Ø NO and PGE 2 which dehydrates readily into PGA 2 w171x. Inflammation does not necessarily expose cells Ø to sufficient NO or PGA 2 , individually, to duplicate the results reported by Calmels et al. w108x and Moos et al. w137x. However, inflammatory exudate contains a blend of electrophiles typified by a , b unsaturated aldehydes derived from eicosanoid biosynthesis or lipid peroxidation Žmalondialdehyde, 4-OH-nonenal. w123x; a , b unsaturated ketones derived from

Fig. 3. Dysfunctional p53: response to genomic damage.

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Fig. 4. Epigenetic inactivation of p53 by inflammatory mediators: response to genomic damage.

eicosanoid metabolism Ž15-keto-PGF2 a , 15-KetoPGE 2 , 5-, 12-, and 15-oxo-eicosatetraenoic acid.; and a , b unsaturated ketones derived from albumin dehydrating PGD 2 Ž D12-PGJ2 and 15-deoxy-D12PGJ2 . w172x. Thus, inflammation might expose cells to a mixture of electrophiles in quantities sufficient to impair transactivation by p53. Accordingly, the link between inflammation and cancer will be clarified by discerning the structure–activity relationships and mechanisms that enable electrophilic mediators of inflammation to impair transactivation, conformation and phosphorylation of p53 and other redox sensitive transcription factors involved in genomic surveillance and repair. 3.3. Mechanistic and biological implications Knudson’s hypothesis asserts that tumor formation requires the mutation or deletion of both copies of a tumor suppressor gene w46x. Tumor suppressor p53 conforms to this hypothesis in most cases. For instance, a point mutation in one p53 allele, paired with a loss-of-heterozygosity in the other p53 allele are abundant in tumors. To accommodate Knudsen’s

hypothesis in subsets of tumors with an intact p53 allele paired with a mutant allele, Fearon and Vogelstein w47x proposed the Adominant negativeB effect—most experimental data support this proposal. However, a Adominant negativeB effect does not accommodate Knudsen’s hypothesis with tumors harboring a wild-type allele paired with deleted allele, nor does it explain the tumor incidence and survival rates among p53 Žyry ., p53 Žqry . and p53 Žqrq . mice w48x. Our results may provide a way to accommodate Knudsen’s hypothesis with the special case of p53 Žqry . tissue. Loss of heterozygosity represents one of the AhitsB and sporadic inactivation of the wild-type p53, by the process described by Calmels et al. w108x or Moos et al. w137x, represents the AsecondB hit. Instead of a gene dosage effect, we speculate that the incidence of tumorigenesis is a function of the frequency and duration of the epigenetic impairment of p53 by endogenous or exogenous electrophiles. In other words, if electrophiles impair p53 in cells heterozygous for p53, it would correspond essentially to the Asecond hitB of Knudsen’s hypothesis and it would offer a mechanism other than the dominant negative activity of the mutant to account for oncogenesis.

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4. Cyclooxygenase (COX) isoenzymes and cancer 4.1. COX-2 expression and function in cancer Numerous investigations have established the medical importance of the COX-1 and COX-2 isoenzymes w173–184x. Experimental and clinical data fit the notion that disease-restricted expression of the COX-2 gene helps to govern their respective roles in physiological and pathological processes w185x. Restricted expression of COX-2 in neoplasms can occur, distinct from inflammation. Inflammation is neither an intermediate step nor a risk factor for inherited syndromes like Familial Adenomatous Polyposis. Furthermore, several types of neoplastic and pre-neoplastic tissue overexpress COX-2, compared to adjacent non-involved tissue ŽTable 3.. In some of these tissues, COX-2 expression appears causal, not incidental, and its expression is not associated with any inflammatory process. The Min mouse model of intestinal polyposis, in particular, shows that expression of COX-2 facilitates progression to neoplasia w186–189x. For instance, homologous disruption of the COX-2 gene diminishes polyp formation in Min mice by ; 80% w188, 189x. In colon cancer, or related animal models such as the Min mouse, COX-2 exerts an oncogenic effect by modifying, i.e. aggravating, the pathological consequences of mutations in the adenomatous polyposis coli Ž APC . tumor suppressor gene. Once COX-2 protein accumulates, following induction or stabiliza-

tion of COX-2 mRNA, it catalyzes the formation of prostaglandins and reactive by-products that may accelerate the carcinogenesis process. COX-2 catalysis can aggravate carcinogenesis via at least three mechanisms, each of which has some experimental support. First, accumulation of arachidonic acid favors apoptosis, and depletion of arachidonic acid favors cells survival w190–193x. Accordingly, COX-2 catalysis depletes an apoptotic signal by lowering the intracellular level of free arachidonic acid. The second, more conventional mechanism, is that prostaglandins Že.g. PGE 2 . formed by COX-2 catalysis modulate cellular processes that govern cell growth and differentiation. For instance, PGE 2 inhibits apoptosis by inducing the Bcl-2 protooncogene w194x and enhances angiogenesis and adhesion by modulating integrin expression w195,196x. PGE 2 ordinarily elevates intracellular cyclic AMP, which suppresses apoptosis in the gastrointestinal tract w197x. Accordingly, COX-2 catalysis generates products with several biochemical effects converging at suppression of apoptosis. A third mechanism involves the effects of malondialdehyde, an endogenous mutagen w110– 116x, generated coordinately with the PG endoperoxides, PGG2 and PGH 2 . Exogenously applied malondialdehyde is not carcinogenic in SENCAR mice w117x; however, this result is consistent with the fact that it exists predominately as an anion that cannot traverse the plasma membrane very readily w123x. This trait makes it difficult to compare the consequences of endogenous production of malondialde-

Table 3 Disease-restricted expression of COX-2 in oncology Organ system

Observation

Incidence

Colon carcinoma w219x Colon adenocarcinoma w220x Breast tumor w220x Lung tumor w220x Gastric tumor w221x Head and neck squamous cell carcinoma ŽHNSCC. w222x Pancreatic cancer w223x

COX-2 mRNA at site of pathologly) the non-involved site COX-2 protein at site of pathology) non-involved site COX-2 protein at site of pathology) non-involved site COX-2 protein at site of pathology) non-involved site COX-2 protein at site of pathology) non-involved site Mean COX-2 mRNA in HNSCC 150-fold) normal volunteers

5r5 subjects 5r7 subjects 11r20 subjects 18r20 subjects 73r104 subjects

Mean COX-2 mRNA in pancreatic cancer 60-fold) adjacent non-involved tissue. COX-2 protein at site of pathology) non-involved site COX-2 levels ) in tumors with larger sizes and deeper invasion

9r10

Colon carcinoma w224x Cervical cancer w225x

F.A. Fitzpatrickr International Immunopharmacology 1 (2001) 1651–1667

hyde at a porous nuclear membrane with the consequences of its exogenous administration exterior to the plasma membrane barrier w117,118x. Presumably, overexpression of COX-2 derives from somatic mutations that persistently activate signaling pathways Že.g. ras, various growth factor receptor tyrosine kinase pathways. w198,199x or from factors that regulate COX-2 mRNA stability w200,201x in some neoplastic tissue. As one might expect, COX-2 overexpression is not observed in all tumors. For instance, in 13–14% of colorectal adenomas, the methylation of CpG islands near exon 1 silences COX-2 expression w202x. This implies that adenomas lacking a functional COX-2 gene, due to its epigenetic silencing, should not respond to treatment with COX-2 specific inhibitors. Likewise, according to Vogelstein’s model of colon cancer progression w203,204x, these adenomas should remain in a pre-neoplastic state and resist transformation into adenocarcinoma longer than adenomas with COX-2. This can be tested experimentally. 4.2. Non-steroidal anti-inflammatory drugs (NSAIDs) and cancer preÕention As noted in Section 2.4, administration of various NS AIDs retards development of malignant colon tumors, or causes pre-malignant adenomas to regress, thereby lowering the incidence and mortality of colon cancer w48–76x. In other types of solid tumors, especially those that do not have precursor lesions, preliminary investigations suggest that NSAIDs do not always confer such remarkable benefits w205–209x. At present, there are no explicit guidelines for the use of NSAIDs as preventive agents in oncology w210x. When these guidelines are established, it will be important to treat them as guidelines, not dogma —we still have much to learn about the preventive mechanisms of NSAIDs in cancer. For examples, inhibition of COX catalysis appears sufficient, but not necessary, for benefit, if one considers the results with exisulind and the R-enantiomer of flurbiprofen ŽE-7869., two atypical NSAID analogs w211x. Recent pre-clinical studies by its manufacturer suggest that Exisulind Žsulindac sulfone. induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. Certain precancerous and cancerous cells may overexpress this enzyme, accounting for some selective toxicity

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of exisulind. Nominally, exisulind acts independently of COX-1 or COX-2 inhibition w212x; however, investigations with human tumors transplanted to rodents challenge this assertion w213x. Data with the R-enantiomer of flurbiprofen are equally provocative, and promising. Flurbiprofen occurs as a racemic mixture of R- and S-enantiomers like other NSAIDs in the 2-arylpropionic acid family. The S-enantiomers of NSAIDs, including flurbiprofen, are typically 100-fold more potent as inhibitors of COX enzymes, compared to the R-enantiomers. Clearance of the enantiomers is also stereoselective in both humans and rats. Importantly, metabolic inversion of R-flurbiprofen ŽCOX inactive. into S-flurbiprofen ŽCOX inhibitor. was not detected after oral administration of R-flurbiprofen to humans w214x. These latter data strengthen the argument that pharmacological effects of R-flurbiprofen in humans are not attributable to inhibition of COX isoenzymes. Animal experiments affirm that this agent might confer benefit in human disease w215–218x. In the Min mouse, a model of familial adenamatous polyposis, R-flurbiprofen prolongs survival when administered chronically; in the mouse TRAMP model of human prostate cancer, R-flurbiprofen lowered the incidence of metastasis in animal treated with a high fat diet. In these studies w215–218x, investigators took great pains to assure that results were not due to metabolic inversion of R-flurbiprofen ŽCOX inactive. to S-flurbiprofen ŽCOX inhibitor.. Nevertheless, there always remains a formal possibility that this occurs in rodent models.

5. Conclusion Persistent inflammation is a significant risk factor for several types of cancer. This phenomenon seems closely related to granulocytic secretion of genotoxic electrophiles—low exposures over a period of years elevate the risk for an oncogenic mutation. An implication of this model is that anti-inflammatory agents that reduce the granulocytic contribution to genomic instability will confer medical benefit in individuals at risk for cancer from their inflammatory disorder. Oddly, benefits from anti-inflammatory agents that actually reduce granulocytic inflammation are the exception, not the rule. The preventive benefit con-

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ferred by NSAIDs in colon polyps originates from their effects on cylooxygenase in the adenomatous tissue, or surrounding tissue, not from their effects on granulocytes. The recent failure of b-carotene anti-oxidant trials as a cancer prevention method accentuates the gap between the hypotheses driving these interventions and their successful implementation. It is difficult to abandon these hypotheses, leaving investigators with chemical factors other than electrophiles, such as the cytokines described by Nowicki et al. w226x, Hudson et al. w227x and Lin et al. w228x, as alternative explanations.

w8x

w9x

w10x

w11x

Acknowledgements w12x

The Huntsman Cancer Foundation, the National Cancer Institute ŽP30 CA 42014., and the National Institute of Allergy and Infectious Diseases RO1 AI 26730 provided funding. FAF is the Dee Glenn and Ida W. Smith Chair of Cancer Research. We thank Dr. Ernest Hawk, MD MPH from the Division of Cancer Prevention at the NCI for providing current, comprehensive information on NSAIDs and colorectal cancer prevention.

w13x

w14x

w15x

w16x

References w17x w1x Morson BC. Precancer and cancer in inflammatory bowel disease. Pathology 1985;17:173–80. w2x Ekbom A, Helmnick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer, a population based study. N Engl J Med 1990;323:1228–33. w3x Choi PM, Zelig MP. Similarity of colorectal cancer in Crohn’s disease and ulcerative colitis: implications for carcinogenesis and prevention. Gut 1994;35:950–4. w4x Lashner BA. Colorectal cancer in ulcerative colitis patients: survival curves and surveillance. Cleveland Clin J Med 1994;61:272–5. w5x Snapper SB, Syngal S, Friedman LS. Ulcerative colitis and colon cancer: more controversy than clarity. Dig Dis 1998; 16:81–7. w6x Aarnio M, Mustonen H, Mecklin JP, Jarvinen HJ. Prognosis of colorectal cancer varies in different high risk conditions. Ann Med 1998;30:75–80. w7x Ekbom A, Helmick CG, Zack M, Holmberg L, Adami HO.

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