MOLECULAR EPIDEMIOLOGY (L JIAO, SECTION EDITOR)

Blood Biomarkers Linked to Oxidative Stress and ChronicInflammation for Risk Assessment of Colorectal Neoplasia

Francesca Maffei & Sabrina Angelini &Giorgio Cantelli Forti & Patrizia Hrelia

Published online: 20 January 2013# Springer Science+Business Media New York 2013

Abstract Colorectal cancer (CRC) is currently the thirdmost common malignancy in the world. The prognosis ofCRC is directly related to the stage of the cancer at the timeof diagnosis, and survival is significantly better when CRCis diagnosed at an early stage. Consequently, there is anurgent need for the discovery of non-invasive diagnosticmarkers that can reflect the early events linked to colorectalcarcinogenesis. Clinical and experimental data indicate thatchronic inflammation and oxidative stress are involved inthe development of CRC. In this review, we evaluate riskprediction, the diagnostic and prognostic value of bio-markers related to oxidative stress, antioxidant status, oxi-dative DNA damage, and the inflammation process in CRC.

Keywords Colorectal cancer . Risk assessment, Earlydetection . Blood biomarkers . Oxidative stress . Reactiveoxygen species . Lipid peroxidation . Antioxidant enzyme .

Antioxidant micronutients . Oxidative DNA damage .

Chronic inflammation . Cytokines

Introduction

Colorectal cancer (CRC) is a major public health problemaccounting for more than one million new cases and ap-proximately half a million deaths worldwide every year [1].CRC is the third most commonly diagnosed cancer in theworld and the second leading cause of death from cancer [2,3]. The prognosis of CRC is directly related to the stage ofthe cancer at the time of diagnosis, and survival is signifi-cantly better for localized cancers. Prospective studies havedemonstrated that CRC mortality can be reduced by thedetection and removal of adenomatous polyps [2, 4].

At present, a great variety of screening methods areavailable for CRC detection including fecal occult bloodtest, colonoscopy, sigmoidoscopy, and double-contrast X-ray; each has its respective advantages and limitations [5–8].In particular, colonoscopy, the standard screening test forCRC, is recommended every 10 years for people ages 50and older who are considered at low risk but colonoscopy isexpensive, invasive, and occasionally results in complica-tions. Moreover, even if screening procedures have a greatadvantage for early detection of CRC, most adults do notreceive regular age and risk-appropriate screening or arenever screened [2]. Consequently, in the recent years,there is an increasing interest in identifying new preventiveapproaches for CRC.

Colorectal Carcinogenesis: The Effect of ChronicInflammation and Oxidative Stress

CRC results from the progressive accumulation of geneticand epigenetic alterations that lead to transformation ofnormal colonic epithelium into colon adenomacarcinoma;this is called the polyp cancer progression sequence [9–11].

F. Maffei (*) : S. Angelini :G. Cantelli Forti : P. HreliaDepartment of Pharmacology, University of Bologna,Via Irnerio 48,40126 Bologna, Italye-mail: francesca.maffei@unibo.it

S. Angelinie-mail: s.angelini@unibo.it

G. Cantelli Fortie-mail: giorgio.cantelliforti@unibo.it

P. Hreliae-mail: patrizia.hrelia@unibo.it

Curr Colorectal Cancer Rep (2013) 9:85–94DOI 10.1007/s11888-012-0156-z

The sequential process of genes mutations and epigeneticalterations is widely believed to cause the initiation andprogression of benign adenomas into malignant adenocarci-nomas, because these mutations affect signaling pathwaysthat regulate the characteristic behavior of cancer. Thesemutations create a clonal growth advantage that leads tothe outgrowth of progressively more malignant cells, whichultimately manifests itself as invasive adenocarcinoma.

Risk factors for CRC include a family history of CRCs,colorectal adenoma, inflammatory bowel disease (e.g.,ulcerative colitis), obesity, tobacco and alcohol abuse, seden-tary lifestyle, and a diet associated with high consumption ofred meat and saturated fat [12, 13].

Evidence indicates that chronic inflammation is a keyrisk factor for CRC in patients with inflammatory boweldisease. The risk of developing CRC increases with longduration and anatomic extension of inflammation in thebowel [11, 14, 15]. It has been proposed that CRC is theresult of a continued active inflammatory response andtissue destruction which cause loss of cellular differentiationand the development of cellular dysplasia [16, 17]. Clinicaland experimental data indicate that chronic inflammation,acting at different stages of the process of carcinogenesis,increases the risk of developing CRC. Chronic inflammationmay cause dysplasia by inducing DNA modifications inintestinal epithelial cells. Indeed, chronic accumulation ofactivated immune cells, for example neutrophils, macro-phages, and dendritic cells, is accompanied by release ofreactive oxygen and nitrogen species, which are known toinduce genomic mutations. Moreover, chronic inflammationis associated with DNA methylation and histone modifica-tion [18, 19]. All these processes have been associated withthe altered expression of genes involved in carcinogenesis,for example p53, APC, K-ras and Bcl-2 [20].

Once formed, dysplastic cells are subjected to the effectof cell-derived growth factors and cytokines which contrib-ute to tumor growth. Tumor necrosis factor-α (TNF-α) isreleased by activated macrophages and T cells, and canpromote inflammation and colitis-associated cancer. TNF-α can initiate carcinogenesis by promoting DNA damage,stimulating angiogenesis, and inducing expression of cox-2which also induces angiogenesis, promoting tumor growth[20]. Inflammation also contributes to colon carcinogenesisby producing oxidative stress which is defined as overpro-duction of oxygen species combined with insufficient pro-tective mechanisms of anti-oxidative defense [21, 22].Oxidative stress causes cellular damage that contributes topathogenesis of the colitis itself and colon carcinogenesis.Initiation of tumor formation in chronically inflamed tissuemight be mediated by reactive oxygen species (ROS) andreactive nitrogen species (RNS), which are released by cellsof the innate immune system. Increased amounts of ROSand RNS, which oxidize nucleic acid, can affect the

regulation of genes that encode factors that prevent carcino-genesis, for example p53, DNA mismatch repair protein,and DNA base excision-repair proteins [11, 20].

Biomarkers: A new Tool for Risk Assessment and EarlyDetection of Cancer

In recent decades scientific communities have defined bio-markers as measurable and quantifiable biological specieswhich serve as indices for health and physiology-relatedassessment, including disease risk [23]. A biomarker is acellular, biochemical, and molecular alteration that can berecognized or monitored and is, therefore, used to objective-ly measure and evaluate normal biological or pathogenicprocesses [24].

Cancer biomarkers are defined as endogenous moleculesor cellular alterations present in tumor tissues or body fluid,the amounts or modifications of which can be indicative oftumor state and progression characteristics of cancer [25].Cancer biomarkers in blood are produced by tumor cells andsecreted or released into the bloodstream of patients. Thusperipheral blood seems to be a readily accessible source ofmaterial with great utility for identification of surrogatemolecular biomarker related with oncology activity. On thebasis of peripheral blood biomarkers, the development ofless invasive and more accessible tests for early detection ofcancer could greatly reduce the worldwide health burden ofcancer.

The purpose of CRC screening is to reduce mortality byreduction of the incidence of advanced disease. However,the utility of colonoscopy is limited by its invasiveness, lackof compliance, and limited access. Currently, there is anurgent need for the discovery of blood biomarkers that canreflect the early events linked to colorectal carcinogenesis.Blood biomarkers are minimally invasive and would behighly attractive for CRC screening because they could beeasily integrated into any health checkup without the needfor an additional stool sample [26–28]. Sensitive and spe-cific blood biomarkers for early CRC diagnosis could re-move a significant obstacle to screening for this disease andact as less invasive alternatives to colonoscopy. Becauseoverall prognosis of CRC depends on tumor stage andremains poor for advanced disease, discovery of peripheralblood biomarkers would also have the potential for greaterpatient compliance with associated public health benefit.

Oxidative Stress Biomarkers

Chronic oxidative stress can cause a continuous local in-flammatory response that induces tissue destruction andregeneration, so-called chronic inflammation, regarded as apreneoplastic state of CRC, by inducing gene mutations,

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inhibiting apoptosis, or stimulating angiogenesis and cellproliferation [19, 20]. Consequently, the availability of bio-markers linked to inflammation and oxidative stress mightenable risk assessment and early detection of CRC.

In the last few years, several blood biomarkers linked toinflammation and oxidative stress have been evaluated as analternative strategy for improving early detection of CRC. Themajor biomarkers investigated are summarized in Table 1.

Prediagnostic serum levels of oxidative stress markers inrelation to subsequent development of CRC have been inves-tigated in a nested case–control study (1,064 CRC cases,1,064 matched controls) in the European Prospective Investi-gation into Cancer and Nutrition cohort (EPIC 1992–2003).The cases and controls were matched (1:1) by age (±2 years atrecruitment), gender, study center, time of day of blood col-lection, and fasting status at the time of day blood collection.Reactive oxygen metabolites (ROM) and ferric reducing abil-ity of plasma (FRAP) were used as indicators of oxidativestress [29••]. ROM assay is a spectrophotometric test thatdetermines the concentration of hydroperoxides and theFRAP assay measures the ability of an antioxidant to reducea ferric complex (Fe3+) to a ferrous complex (Fe2+). In thisEuropean study, with a median follow-up time of 3.7 years forcolon cancer and 3.9 years for rectal cancer, a positive asso-ciation was observed between prediagnostic levels of ROMand the risk of CRC, irrespective of anatomic site. However,this association was apparent only for participants with lessthan 2.63 years of follow-up, suggesting that the associationbetween ROM and CRC risk is a result of ROS production bypreclinical tumors, rather than a casual factor in carcinogene-sis [30]. This study used the ROM as a marker of ROSproduction and FRAP as a marker for detoxification. None-theless, ROM and FRAP were not correlated, and theexpected inverse association between FRAP levels and CRCwas not observed. This may be because of the specific char-acteristics of the FRAP assay, which is largely dependent onthe concentration of specific serum components, for examplealbumin and uric acid. This method is not necessarily assensitive as the ROM assay for detecting changes in freeradical production [31]. Although this study provided novelinsight into oxidative stress and risk of CRC, whether higherlevels of ROS increase the risk of CRC development in thelong term remains unclear.

In the same EPIC cohort, a nested case–control study of1,238 cases and 1,238 matched controls also investigated theassociations between serum concentrations of lipids and lip-oproteins and the risk of CRC [32]. The study showed that theconcentration of high-density lipoproteins (HDL) and theircomponent apolipoprotein A-1 (apoA) were inversely statis-tically significantly associated with CRC risk. For both bio-markers, the observed associations were limited to the colonanatomical subsite, but only the association with HDLremained after exclusion of the first two years of follow-up.

The association between HDL concentrations and CRCrisk has been investigated in three other prospective cohortstudies, two based on North American populations and one ona Finnish population [33–35]. The findings are generally inagreement with those of the EPIC studies, but the smallpopulation size was a limiting factor for reaching statisticalsignificance. HDL may modulate colon carcinogenesisthrough inflammatory pathways. Reduced concentrations ofHDL have been linked with increased circulating concentra-tions of proinflammatory cytokines, for example interleukin(IL)-6 and TNF-α receptors, which stimulate cell growth andcellular proliferation and inhibit apoptosis [36, 37]. Further-more, increased concentrations of such anti-inflammatorycytokines as IL-10 are associated with increased concentra-tions of HDL-cholesterol [38]. Another possible mechanism isby modulation of oxidative stress, because HDL has antioxi-dant activity and can protect against oxidation of LDL-cholesterol [39]. A low concentration of HDL leads to moreoxidized low density lipoprotein (oxLDL) which can increaseintracellular oxidative stress [40]. Low HDL is also a featureof insulin resistance, which, it has been suggested, is involvedin the etiology of CRC [41]. Nevertheless, adjustment of ROMin the EPIC study did not change the association betweenHDL and risk of CRC. This indicates the potential antioxida-tive property of HDL cannot explain the inverse associationbetween HDL and risk of CRC, or that inaccurate measure-ment of ROM resulted in incomplete adjustment [32].

Suzuki et al. [42] have investigated the association betweenserum levels of oxLDL and oxLDL antibody (oLAB) andCRC risk in a case–control study nested in the prospectiveJapan Collaborative Cohort study. Significant positive associ-ation was observed between serum oxLDL levels and risk ofCRC, whereas no association between serum oLAB and CRCrisk was found. However, only 161 CRC cases and 395controls were included in this study, and no analysis stratifiedfor time before diagnosis could be conducted. Consequentlyfurther investigations are needed to clarify whether serumoxLDL is a biomarker for predicting risk of CRC.

Oxygen radicals react with polyunsaturated fatty acidresidues in phospholipids. One of the most abundant carbonylproducts of lipid peroxidation is malondialdehyde (MDA),which reacts with DNA to form adducts, contributing signif-icantly to the occurrence of cancer [43]. Higher MDA levelshave been found in tumor colon tissues than in accompanyingnormal mucosa, and MDA has also been found to be associ-ated with more malignant phenotype [44]. Increased level ofMDAwere observed in urine of patients with CRC comparedto control subjects [45]. In patients with advanced inoperableCRC, serumMDA concentration is much higher than in thosewith primary operable CRC [46]. Surinenaite et al. [47] eval-uated the antioxidant status in response to surgical treatmentand red blood cell transfusion among 65 stage II/III CRCpatients. Among nontransfused patients MDA levels were

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Table 1 Blood biomarkers linked to oxidative stress and inflammation investigated for risk assessment of colorectal cancer

Biomarkers Study design Authors

Reactive oxygen metabolites in plasma and ferric-reducingability of plasma

Case–control study nested in a prospectivecohort study

Leufkens et al. [29••]

High-density lipoprotein in plasma. Apolipoprotein A-1 in plasma Case–control study nested in a prospectivecohort study

Van Duijnhoven et al. [32]

High-density lipoprotein in plasma Prospective cohort study Schoen et al. [33]

High-density lipoprotein in plasma Prospective cohort study Ahmed et al. [34]

High-density lipoprotein in plasma Prospective cohort study Ahn et al. [35]

Oxidized low-density lipoprotein and oxidized low-densitylipoprotein antibody in serum

Case–control study nested in a prospectivecohort study

Suzuki et al. [42]

Malondialdehyde levels in plasma Patients with different stages ofcolorectal cancer

Surinenaite et al. [47]

Superoxide dismutase and glutathione peroxidase activity inplasma

Case–control study Dincer et al. [49]

Superoxide dismutase, catalase, and glutathione peroxidase activityin plasma

Case–control study Chang et al. [50]

Catalase activity in plasma Case–control study Gur et al. [51]

Glutathione level in serum; glutathione peroxidase,glutathione-S-transferase, and glutathione reductase activity inserum

Patients with different types ofgastrointestinaltract tumor

Scibior et al. [52]

Glutathione-S-transferase isoenzymes activity in plasma and innormal and tumor tissue

Case–control study Nomani et al. [54]

Superoxide dismutase, catalase glutathione peroxidase, andglutathione-S-transferase activity and clastogenic factor in plasma

Case–control study Maffei et al. [55]

Antioxidant micronutrient concentration in plasma Case–control study Jiang et al. [57]

Antioxidant micronutrient concentration in plasma Case–control study nested in a prospectivecohort study

Wakai et al. [58]

Vitamins C, E, and carotene concentrations in serum Case–control study Breuer-Katschinski et al.[59]

8-Oxo-7,8-dihydro-2′-deoxyguanosine in leukocyte DNA Case–control study Gavkowski et al. [69]

8-Oxo-7,8-dihydro-2′-deoxyguanosine in leukocyte DNA Case–control study Guz et al. [70]

8-Oxo-7,8-dihydro-2′-deoxyguanosine in leukocyte DNA;Vitamin A, C, and E level in plasma

Case–control study Obtulowicz et al. [71]

8-Oxo-7,8-dihydro-2'deoxiguanosine level in plasma Cross-sectional study Sato et al. [72]

C-reactive protein, tumor necrosis factor-α, interleukin-6,1β, and 8–10 levels in plasma

Randomized, controlledclinical trial

Hopkins et al. [75]

C-reactive protein, tumor necrosis factor-α, and interleukin-6levels in plasma

Colonoscopy-based cross-sectionalstudy

Kim et al. [37]

C-reactive protein, tumor necrosis factor-α, and interleukin-6levels in plasma

Cohort study Il’yasova et al. [79]

C-reactive protein in plasma Case–control study McMillan et al. [80]

C-reactive protein in serum Case–control study Engwegen et al.[81]

C-reactive protein in plasma Case–control study nested in a prospectivecohort study

Erlinger et al. [82]

C-reactive protein in plasma Case–control study nested in a prospectivecohort study

Otani et al. [83]

C-reactive protein in serum Prospective cohort study Gunter et al. [84]

C-reactive protein in plasma Prospective cohort study Zhang et al. [85]

C-reactive protein in serum Case–control study nested in a prospectivecohort study

Ito et al. [86]

C-reactive protein, tumor necrosis factor receptor, andinterleukin-6 levels in plasma

Case–control study nested in a prospectivecohort study

Chang et al. [88••]

Soluble receptor for advanced glycation end-productsin plasma

Prospective cohort study Jiao et al. [90]

Macrophage inhibitory cytokine-1 levels in serum Polyp prevention trials Brown et al. [92]

C-reactive protein and amyloid in serum Prospective cohort study Toriola et al. [93]

C-reactive protein, serum CD26, and complement 3tissue inhibitor of metalloproteinases 1 levels in blood

Case–control study Tao et al. [94]

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significantly lower in patients with stage II cancer (n=15)when presurgical and both postsurgical periods were com-pared (P=0.003 on day 7 and P=0.002 on day 14); amongpatients with stage III cancer (n=22) MDA levels were lower14 days postsurgery only (P=0.003). Among transfusedpatients, when post and pre-surgical periods were comparedMDA levels were lower for patients with stage II cancer only(n=22; P=0.008). These observations suggest the postsurgi-cal period affects changes in such antioxidative indicators asMDA. MDA might be related to CRC carcinogenesis andprogression and may be used as a biomarker for clinicalprognosis and surveillance of CRC [43].

Antioxidant Enzymes and Antioxidant Vitamins as PotentialBiomarkers

Tissue antioxidant enzymes, for example superoxide dismu-tase (SOD), catalase (CAT), glutathione reductase (GR),glutathione peroxidase (GPX), and glutathione-S-transferase(GST), are crucially important to redox balance and thehealthy state of the human body, and are altered in cancerpatients [48, 49]. A decrease in antioxidants may disrupt thebalance between pro and anti-oxidants, leading to cellulardamage and, ultimately, malignant transformation.

Only few case–control studies have been performed onantioxidant enzyme activity in the serum or plasma of CRCpatients, and the overall results are not conclusive. In acase–control study (36 patients with CRC and 40 healthysubjects) SOD, CAT, and GPX activity was significantlylower in the plasma of CRC patients than in that of controls[50]. Gur et al. [51] also detected lower CAT activity in theplasma of 40 CRC patients than in that of 29 healthyvolunteers. In a small case–control study, GPX activitywas lower whereas SOD activity was higher in the plasmaof 26 CRC patients compared with a control group [49].Glutathione (GSH) level and GPX, GST, and GR activityhave been evaluated in serum from 165 patients with differenttypes of gastrointestinal tract tumor before and after surgery(30 with gastric cancer, 20 with liver tumors, 65 with CRC,and 50 with metachronous CRC liver metastases) and 50healthy controls. Greater GST activity has been detectedCRC patients before surgery than in a control group, whereasno significant differences were detected for GPX or GRactivity and GSH level [52].

Cytosolic GSTs comprise multiple isoenzymes—GTSM,GSTT, GSTP, and GSTA classes [53]. The efficacy of usingplasma GSTs activity as a biomarker of risk of CRC hasbeen investigated by Nomani et al. [54]. GSTs activity wasmeasured in the plasma of 39 control individuals and in theplasma, tumor tissue, and normal tissue adjacent to a tumor,taken at colonoscopy, of 60 patients with CRC. GSTs activ-ity was significantly higher in tumor biopsies than in thosecollected from normal adjacent tissues. The increased

activity of total GSTs may be because of overexpression ofisoenzymes of GSTs in response to the induction of metabo-lism in tumor cells. Furthermore, plasma GSTs activitywas significantly higher in CRC patients than in normalindividuals, suggesting plasmaGSTs could be a potential non-invasive biomarker linked to CRC risk.

Increased production of superoxide radicalsmay induce therelease of chromosome-damaging material, the so-called clas-togenic factors (CFs), in circulating plasma. Recently, GR,SOD, CAT, and GST enzyme activity and CFs have beendetermined in plasma from 25 CRC patients, 26 patients withcolorectal polyps, and 31 controls [55]. The formation of CFsin plasma from study population was assessed as micronucleiinduction in peripheral blood lymphocytes. Significant alter-ation of the activity of CAT, GR, and SOD was detected inCRC patients in comparison to controls and polyp patients,whereas GST activity was not modified. In particular, CATand GR activities decreased, whereas SOD activity increasedin the plasma of patients with CRC compared with control andpolyp groups. Moreover, an increase of CFs has been detectedin plasma of CRC patients in comparison to the control group.CFs were associated with the increase of SOD activity, and thedecrease of both CAT and GR enzyme activities detected inCRC group. Reduction of CAT and GR activity and increasedSOD activity in CRC patients could lead to high levels ofH2O2. H2O2 can act as an initiator of a series of cascade eventsrelated to oxidative stress—for example lipid peroxidation—leading to the formation of CFs that can affect DNA andcontribute to the initiation of colon carcinogenesis.

Antioxidant micronutrients, for example carotenoids, reti-nol, and α-tocopherol, have been shown to scavenge ROS andprotect against oxidative stress [56] Two studies conducted inJapan have examined the association between serum or plasmaantioxidant micronutrient concentrations and risk of colorectaladenomas or CRC. One was a population-based case–controlstudy of 224 cases and 230 controls [57]; the other was anested case–control study of 116 cases and 298 controls withina prospective cohort [58]. Both studies suggested an inverseassociation between blood levels of carotenoids and risk ofcolorectal neoplasmas. A gender-specific association was alsofound [57, 58]. In contrast, no association between serumconcentrations of vitamins C and E and carotene was foundin a population-based case–control study in Germany thatincluded 105 cases and 105 controls [59]. Disparities regardingconfounding factors (e.g. smoking, alcohol drinking) or sam-ple size among different study populations may explain, tosome extent, the divergent results obtained. Investigations ofvitamins C and E are sparse, and the results do not enable clearevaluation of the association between plasma levels of thesemicronutrients and CRC risk [60, 61]. On the whole, evidenceof a relationship between plasma antioxidant micronutrientconcentrations and CRC risk is still limited and inconsistent.A review article proposed that a gamma-tocopherol-rich

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mixture of tocopherol is a very promising cancer-preventiveagent and warrants extensive future research [62]. Prospectivecohort studies are needed to elucidate whether plasma levelsof antioxidant micronutrients can be useful biomarkers forearly detection of CRC.

Oxidative DNA Damage Biomarkers

Oxidatively damaged DNA is involved in the physiologicalchanges linked to degenerative diseases and cancer [63, 64].ROS interact with genetic material forming several mutagenicmodified DNA bases [65•]. 8-oxo-7,8-dihydro-2'-deoxygua-nosine (8-oxodG) is a typical biomarker of oxidative stress,which may be involved in carcinogenesis [66, 67]. The pres-ence of 8-oxodG residues in DNA leads to GA→TC trans-versions. [68]. 8-oxodG is formed in DNA either by directoxidation of nucleic acids or can be incorporated from thenucleotide pool by DNA polymerases, the latter process beingan important source of DNA oxidation and genome instability[66, 67]. Studies have investigated a possible association be-tween the level of 8-oxodG in leukocyte DNA and CRC risk.Gackowski et al. [69] found significantly higher levels of 8-oxodG in lymphocytes of 45 CRC patients (26 males and 19female with an median age 63 years) than in DNA of 55healthy controls (25 males and 30 females with a median age60 years). One case–control study discovered significantlyhigher levels of 8-oxodG in leukocyte DNA of patients withcolon adenomas (n=35) and carcinomas (n=50) than in that ofhealthy subjects (n=105). Furthermore 8-oxodG levels weresignificantly higher in DNA isolated from cancer tissue ofcarcinoma patients than in that from normal tissue [70].Obtulowicz et al. [71] have examined the same biomarkerslinked to oxidative stress in 89 patients with CRC, 77 patientswith benign adenoma, and 99 healthy volunteers. Interestingly,they observed gradual depletion of vitamins A, C, and E inplasma from adenoma and CRC patients and significantlymore 8-oxodG in the leukocytes and urine of CRC and ade-noma patients in comparison with healthy controls. Takentogether these findings indicate that oxidative stress is inducedat an early (adenoma) stage of colon carcinogenesis, andincreases during disease progression. Consequently, 8-oxodGin leukocyte DNA seems a promising biomarker for CRC risk.Association of plasma levels of 8oxodG with risk of adenomaandCRC has been examined in a small cross-sectional study of58 patients with adenoma, 32 with early cancer, 25 withadvanced cancer, and 36 without polyps or cancer (controls).The results of the study suggested oxidative stress was associ-ated with increased risk of colorectal adenoma and cancer [72].

There has been consistent interest in investigating theeffect of modulation of calcium and vitamin D3 on oxidativeDNA damage. One animal study showed that expression of8oxodG was significantly augmented with complete loss ofvitamin D receptor. It has been suggested that the action of

1,25-dihydroxyvitamin D3 (1,25D3) is necessary to protectagainst nutrition-linked hyperproliferation and oxidativeDNA damage [73]. A randomized clinical trial tested theeffects of treatment with calcium and vitamin D3 for monthson 8oxodG levels in biopsies of normal colorectal mucosa of92 patients with colorectal adenoma. This pilot study supportsthe hypothesis that 8oxodG labeling in colorectal crypts is atreatable oxidative DNA damage biomarker of risk of colo-rectal neoplasma [74]. The same clinical trial study also foundthat the treatment with vitamin D3 or calcium supplementalone resulted in reduction of tumor-promoting inflammationbiomarkers. C-reactive protein (CRP), TNF-α, IL-6, IL-1β,and IL-8 were evaluated as pro-inflammatory and IL-10 wasan anti-inflammatory marker [75].

Inflammation Biomarkers

Accumulating evidence suggests that systemic inflamma-tion might be a plausible mechanism of colon carcinogene-sis [19, 20]. Tissues can produce and release inflammatorycytokines that are potentially procarcinogenic. IL-6 seems tostimulate cell growth and inhibit apoptosis [76]. TNF-α isan important cytokine involved in regulation of cytokinesduring inflammatory responses [77]. The inflammatory CRPup-regulates expression of adhesion molecules and stimu-lates release of IL-1, IL-6, IL-18, and TNF-α from mono-nuclear phagocytes [78]. A few studies have evaluatedplasma levels of CRP, IL-6, and TNF-α and their relation-ship with colorectal neoplasia. In a colonoscopy-based cross-sectional study of 242 colorectal adenoma cases and 631controls the prevalence of colorectal adenomas was associatedwith higher circulating levels of IL-6 and TNF-α and, to alesser extent, with CRP [37]. Among 2.438 older adults (aged70-79 years) participating in the Health Aging and BodyComposition study, the association between circulating levelsof IL-6, CRP, and THF-α and risk of incident cancer wereexamined. During average 5.5 years of follow-up 296 incidentcancers were ascertained and 14.5%were found to have CRC.In this prospective study, baseline levels of CRP were posi-tively associated with incident CRC and levels of IL-6 wereinsignificantly associated with increased risk of CRC. How-ever, this study was limited by small number of site-specificcases [79].

Retrospective case–control studies have compared CRPconcentrations in CRC patients and healthy controls, and havereported at least tenfold higher concentrations in the cancerpatients [77, 80, 81]. In contrast, prospective studies investigat-ing the association of prediagnostic circulating C-reactive pro-tein concentration with development of CRC have beeninconsistent. Erlinger et al. [82] in a nested case–control studyin the CLUEII cohort (Give Us A Clue to Cancer and HeartDiseases) found elevated plasma CRP concentrations amongthe study subjects who subsequently developed colon cancer.

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Two prospective studies based on a Japanese population [83]and a cohort of Finnish male smokers [84] also support anassociation between CRP and CRC, but there was no clearrelationship between CRP and CRC in a Women’s HealthStudy [85] or in the Japan Collaborative Cohort Study [86].In a recent meta-analysis, including 1,159 CRC cases and37,896 controls, only a weak positive association betweencirculating high-sensitivity CRP concentration and CRC riskwas identified. The summary relative risks (RR) per one unitchange in natural log-transformed high-sensitivity CRP was1.12 (95 % CI 1.02–1.25) for CRC [87]. The associationbetween the risk of CRC and levels of the plasma inflammatorymarkers CRP and IL-6 and the soluble tumor necrosis factorreceptor (sTNFR-2) have recently been investigated in a nestedcase–control analysis among women enrolled in the Nurses’Health Study who provided blood samples at baseline and werefollowed up for 14 years. The results obtained from 280 casesfor CRC and 555 controls have shown a positive associationbetween baseline plasma TNFR-2 level, but not CRP or IL-6level, and subsequent risk of CRC [88••]. Several novel inflam-matory markers have been examined in relation to risk of CRC.In a prospective study of Finnish male smokers (255 cases and485 randomly selected controls), a anti-inflammatory marker,soluble receptor for advanced glycation end-products(sRAGE), was shown to be inversely associated with risk ofCRC [89]. Their investigation on 158 cases with colorectaladenoma and 203 polyp-free controls also found an inverseassociation between sRAGE and risk of colorectal adenoma[90]. Interestingly, low sRAGE levels have been associatedwith enhanced in vivo oxidative stress and endothelial dysfunc-tion in patients with type 2 diabetes, as reflected by urinary 8-iso-PGF2a [91]. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) mediates nonsteroidal anti-inflammatory drug(NSAID) protection from colonic polyps in mice and is linkedto the development of colorectal carcinoma in humans. In thePolyp Prevention Trial, serumMIC-1/GDF15 levels were mea-sured in 623 subjects with removed polyps. This study found acomplex relationship between serum levels of MIC-1/GDF15and the presence, recurrence, and/or protection from colonicpolyposis. The authors suggest that MIC-1/GDF15 is the firstserum marker having any relationship with the presence ofcolonic adenomas with potential clinical utility [92]. Two stud-ies have evaluated the utility of blood inflammatory biomarkersin early detection of CRC. In the prospective Women’s HealthInitiative Study [93], women with elevated concentrations ofboth CRP and serum-amyloid A had an increased risk ofcolon cancer (OR=1.50, 95 % CI 1.12–2.00, P=0.006)compared with those with low concentrations (by quintile).Further analysis indicated that change of the biomarkers inthree years did not predict risk of colon cancer. Anotherstudy in Germany compared the sensitivity of fecal occultblood tests (FOBTs) and combined blood-based inflamma-tory markers for detection of advanced colorectal adenoma

and CRC among 179 patients with CRC, 193 patients withadvanced adenoma, and 225 adenoma-free controls [94].Blood levels of CRP, serum CD26, complement 3, andtissue inhibitor of metalloproteinases 1 were different be-tween CRC patients and controls. However, although thecombined four markers had specificity of 97 % for detect-ing CRC, the diagnostic performance of these four bloodmarkers for advanced adenoma and CRC was worse thanperformance of the FOBTs. Combinations of iFOBT andblood markers were suggestive of a slight improvement indetection of advanced adenomas. Taken together, allthese findings confirm the involvement of chronic in-flammation in the pathogenesis of CRC, and emphasize theneed for prospective investigations to identify specific inflam-matory blood markers to assess CRC risk. The newly identi-fied inflammatory biomarkers will further our understating ofthe origin of inflammatory conditions and furnish more insightinto CRC etiology. However, the value of inflammatory bio-markers in early detection of CRC may be limited.

Conclusion

In the past 10 years, substantial effort has been devoted to asearch for non-invasive biomarkers for predicting CRC risk. Ahandful of observational studies have evaluated specific plas-ma oxidative biomarkers—oxidative stress metabolites, anti-oxidant enzymes, antioxidant vitamins, and oxidative DNAdamage—in case–control studies. A few prospective studieshave evaluated risk assessment of CRC using a variety ofinflammatory biomarkers. However, prospective evidence ofan association between biomarkers of oxidative stress andCRC risk is still limited. Generally speaking, all the findingssupport the concept that both chronic inflammation and oxida-tive stress are key aspects of colorectal carcinogenesis, but donot enable clear identification of specific biomarkers for riskassessment and early detection of CRC. Because of the com-plexity of colorectal carcinogenesis, it is plausible that mea-surement of one or few plasma biomarkers separately does notprovide sufficient information about their diagnostic value.Combined measurement of pro and anti-oxidant exposuremay be an appropriate technique for evaluation of oxidativestress-related conditions in CRC [95]. Large prospective pop-ulation studies with long follow-up and repeated measure-ments of several blood biomarkers related to oxidative stress,antioxidant status, and inflammation pathogenesis are war-ranted to reveal sensitive and specific biomarkers for diagnosisand prognosis of CRC, and risk prediction. Use of these bloodbiomarkers in clinical practice may lead to the discovery ofalternative and effective strategies for early detection of CRC.

Disclosure No potential conflicts of interest relevant to this articlewere reported.

Curr Colorectal Cancer Rep (2013) 9:85–94 91

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