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Effects of NSAIDs on the risk factors of colorectal cancer: a mini review

Effects of NSAIDs on the risk factors of colorectal cancer: a mini review Evidence from epidemiological and experimental studies has shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer (CRC). The function of NSAIDs and the molecular targets for chemopreventive effects on CRC have been extensively studied and their data were reported. However, the relation between NSAIDs and the risk factors of CRC have not been fully elucidated yet. Thus, relations between NSAIDs and the risk factors of CRC, such as overweight and obesity, alcohol, aging, hypertriglyceridemia and smoking, are summarized with our data and with recent reported data in this review. Keywords: Non-steroidal anti-inflammatory drugs, Colorectal cancer, Risk factors, Chemoprevention Background pathway. The constitutive enzyme COX-1 has low ex- Non-steroidal anti-inflammatory drugs (NSAIDs) relieve pression in normal human colorectal tissue, whereas the pain, reduce inflammation, lower fevers and prevent inducible enzyme COX-2 is elevated in tissue involved blood from clotting. Thus, NSAIDs are used to treat in- in inflammation and in cancer. Traditional NSAIDs flammatory conditions such as arthritis. One of the trad- block the actions of both COX-1 and COX-2, and select- itional NSAIDs, aspirin, was used to protect against ive COX-2 inhibitors are a special category of NSAIDs. heart disease. Conversely, NSAIDs can increase the risk In addition, aspirin can inhibit proliferation and induce of gastrointestinal (GI) bleedings/ulcer and interfere with apoptosis of colon cancer cells [2]. The inhibition and kidney function. The severity of side effects increases by induction by aspirin include the following: (i) the inter- taking NSAIDs longer. ruption of nuclear factor kappa B (NF-κB), (ii) the inter- A large number of epidemiological and experimental ruption of extracellular signal-regulated kinases, (iii) the studies have shown that NSAIDs reduce the risk of colo- induction of caspase 8 and 9, and (iv) the inhibition of rectal cancer (CRC). Meta-analysis of randomized trials β-catenin signaling. revealed that use of aspirin for approximately 5 years re- As shown above, the function and molecular targets of duces incidence and mortality due to CRC by 30–40 % NSAIDs have been well studied, and several pieces of after 20 years of follow-up [1]. evidence have shown their chemopreventive effects on The effectiveness of NSAIDS may be attributed to CRC. However, the relation between NSAIDs and the their potent inhibition of cyclooxygenase (COX) en- risk factors of CRC have not been well examined. In this zymes because COX-2 expression and prostaglandin review, such relationships are summarized with our data (PG) E synthesis are elevated in CRC. The COXs/PGH and recent reported data in the text, Table 1 and 2. synthases have two enzymes, COX-1 and COX-2, and COX is the limiting enzyme of the PG synthesis Risk factors of colorectal cancer A risk factor is any attribute, characteristic or exposure * Correspondence: mimutoh@ncc.go.jp 1 of an individual that increases the likelihood of develop- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 TsukijiChuo-ku, ing a disease or injury [3]. In the case of cancer, it is de- Tokyo 104-0045, Japan fined as factors that increase the chance of developing Division of Carcinogenesis and Cancer Prevention, National Cancer Center cancer. Some people with several risk factors never de- Research Institute, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan Full list of author information is available at the end of the article velop cancer. There is an intensity of correlation © 2016 Hamoya et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hamoya et al. Genes and Environment (2016) 38:6 Page 2 of 7 Table 1 Effects of NSAIDs on risk factors of CRC cause chronic low-grade inflammatory states, increased proliferation and angiogenesis, and promote colon car- Risk factors of CRC NSAIDs effects on each factors cinogenesis [12, 13]. Obesity Lose weight and reduce the BMI The use of NSAIDs is associated with reduced risk of Alcohol Increasing risk of GI bleeding due to alcohol inflammation-associated cancers, and obesity-related Aging Slowing cancers are included in inflammation-related cancers Hypertriglyceridemia Improvement [14]. Compared with non-users of NSAIDs, lower risk of Smoking ー obesity-related cancers in NSAID users (hazard ratio BMI body mass index, CRC colorectal cancer, GI gastrointestinal (HR) = 0.88; 95 % confidence interval (CI), 0.85–0.92) NSAIDs Non-steroidal anti-inflammatory drugs has been reported [14]. Although the preventive effects of aspirin and NSAIDs on obesity-related cancers are in- between risk factors and cancer. Thus, there might be conclusive, there are several reports showing that aspirin some weak risk factors of which we are not aware. reduced risks of obesity-related cancers including CRC, Several risk factors of CRC have been demonstrated to particularly among obese people. In the Aspirin/Folate date. The World Health Organization (WHO) lists fac- Polyp Prevention Study, a randomized controlled trial of tors that are convincing evidence for the risk of CRC in aspirin and folic acid to prevent colorectal adenoma, a daily life as follows: (i) consuming red meat, (ii) consum- daily dose of 325 mg aspirin reduced the risk ratio for ing processed meat, (iii) alcoholic drinks (men), (iv) body advanced adenomas compared with placebo among fatness / abdominal fatness, and (v) adult attained height obese subjects (relative risk (RR) = 0.44; 95 % CI, 0.17– increase [4]. Other risk factors are reported as aging [5] 1.10) but not among those with normal weight (RR = and a family history of CRC. Several medical histories of 1.23; 95 % CI, 0.55–2.77) [15]. In the CAPP2 study that diseases are known to increase the risk of CRC, such as recruited participants with Lynch syndrome, CRC risk (i) genetic predisposition including familial adenomatous was 2.41x greater for obese participants (95 % CI, polyposis and hereditary nonpolyposis CRC, (ii) high- 1.06–2.96; P = 0.03) than for underweight and normal- risk adenoma, (iii) inflammatory bowel disease, (iv) type- weight participants, and the obesity-related excess risk 2 diabetes, and (v) hypertriglyceridemia [6]. Moreover, of CRC was confined to those randomly assigned to smoking is a strong factor in the development of colo- the aspirin placebo group (adjusted HR = 2.75; 95 % rectal adenoma [7]. CI, 1.12–6.79, P = 0.03), but the risk was abrogated in From recent published literature, we took particular those taking aspirin [16]. note of overweight and obesity, alcohol, aging, hypertri- PGE levels in rectal mucosa have been reported to be glyceridemia and smoking. The relation between each positively associated with BMI [17]. PGE has been shown risk factor and NSAIDs is described below. to promote colorectal carcinogenesis [18] and metastasis [19] in mouse models, and inhibition of PGE synthesis is Obesity and NSAIDs a potential target for prevention of CRC [20]. Therefore, Obesity is an important risk factor for CRC [8], and decrease of obesity-related CRC by NSAID use could be there is a significant positive correlation between body due to inhibition of PGE production. mass index (BMI) and CRC risk [9, 10]. Visceral abdom- Obesity causes insulin resistance with hyperglycemia inal fat area measured by CT scan is more significantly and hyperinsulinemia, and these contribute to tumor de- associated with colorectal adenoma [11]. Visceral fat ac- velopment [21]. Metformin, an insulin resistance- cumulation causes increases in adipokines such as leptin, improving, anti-diabetic agent, has been reported to re- inflammatory cytokines such as tumor necrosis factor duce risks of various cancers including colon cancer in (TNF) α and interleukin (IL)-6, and growth factors such diabetic and non-diabetic populations [22, 23]. Metformin as insulin-like growth factor (IGF)-I and vascular endo- inhibits cell proliferation via activation of AMP-activated thelial growth factor (VEGF) [12, 13]. These factors protein kinase (AMPK) [24]. Serum adiponectin is de- creased in obese people, and also activates AMPK and in- hibits cell proliferation of colon cancer cells [24]. Recently, Table 2 Effects of NSAIDs plus each risk factors on CRC risk it has been reported that aspirin activates AMPK and in- Risk factors of CRC NSAIDs effects on CRC risk hibits mTOR signaling in colon cancer cells [25]. Not all, Obesity Decreasing [14–16] but several NSAIDs, such as salicylic acid, ibuprofen or Alcohol Protection in a social drinker diclofenac, which have acidic structures, also induce Aging ー AMPK activation [26, 27]. This effect is considered to be a Hypertriglyceridemia Decreasing [49, 50] COX-independent anti-inflammatory property of aspirin Smoking Increasing [57–59] and a subgroup of NSAIDs and may contribute to de- CRC colorectal cancer, NSAIDs Non-steroidal anti-inflammatory drugs crease obesity-related cancer risks. Hamoya et al. Genes and Environment (2016) 38:6 Page 3 of 7 Alcohol and NSAIDs These reports suggest that the carcinogenic effect of In a meta-analysis of cohort and case–control studies, alcohol may be partly through the induction of acetal- there are reports describing moderately increased risks dehyde and inflammation, and NSAID use may effect- of CRC with a dose–response relation for rising alcohol ively protect CRC development in a social drinker. consumption. A polled analysis of eight cohort studies also recorded a dose–response relation between the risk of CRC and the amount of alcohol consumption [28]. Aging and NSAIDs The mechanisms by which alcohol intake exerts its Disruption of normal tissue function dramatically accel- carcinogenic effect are not fully understood yet. Acetal- erates in old age. Aging is the greatest risk factor for dehyde, a metabolite of alcohol, is implicated in esopha- numerous pathologies, including cancer, stroke, neuro- geal carcinogenesis but is not strongly implicated in degenerative disorders, heart disease and type-2 diabetes colorectal carcinogenesis. Recently, single nucleotide [5]. Chronic inflammation is one of the main processes polymorphisms (SNPs) in the alcohol dehydrogenase, that contributes to age-related disease and causes dis- ADH1B, and aldehyde dehydrogenase, ALDH2, of mod- ruption of normal functioning of tissues. Notably, there erate/heavy drinkers were shown to be contributing fac- is a robust increase of mRNA and secretion of numerous tors for CRC [29]. Aspirin and salicylate could inhibit cytokines, chemokines, growth factors and proteases in both human ADH (metabolize ethanol to acetaldehyde) the senescent cells, and these cells may cause a low level and ALDH (degradation of acetaldehyde) activities [30]. of chronic inflammation systemically during aging [39]. To date, the effect of aspirin on acetaldehyde production Yeast, nematodes and flies have been recognized as ex- is not fully understood yet. cellent model systems for studying the underlying mech- Ethanol is known as an irritant for the digestive tract. anism of aging and identifying chemicals altering Ethanol intake is known to be an independent risk factor longevity, mainly because of their short lifespans. A grow- for GI bleeding. It is posited that the GI bleeding risk ing number of reports showed the effects of NSAIDs on from aspirin is high in individuals who consume three the lifespan extension in yeast [40], nematodes [40, 41], or more alcoholic drinks every day [31]. flies [40, 42] and mice [43]. He et al. [40] reported that Several reports suggest that ethanol exposure alters the ibuprofen extended the replicative life span of Saccharo- cytokine levels and inflammatory status in a variety of tis- myces cerevisiae cells by destabilizing the high-affinity sues in vitro and in vivo, including the colon [32, 33]. Fur- tryptophan transporter. He et al. also found that ibuprofen thermore, chronic alcohol intake promoted intestinal caused small size at birth and moderate delay in initiation Min/+ tumorigenesis and tumor invasion in Apc mice [34]. of cell division, which was observed in most long-lived In a report, Wimberly et al. suggested that mast cell- yeast mutants. Meanwhile, celecoxib extended both mean mediated inflammation could be one of the mechanisms and maximum lifespans in C. elegans [41]. The physical by which alcohol promotes intestinal carcinogenesis. health, as indicated by the age-associated decay rate of Recently, Landi and colleagues [35] studied the associ- motor activity, was also significantly improved in ation between SNPs in the IL-6, IL-8, TNFα and PPARG celecoxib-treated nematodes without affecting the nutri- genes and the risk of CRC by a hospital-based case con- tional value. However, no homologs of mammalian COXs trol study. These genes are known to play important have been identified in unicellular organisms, including C. roles in inflammation of the colorectum, and common elegans. Furthermore, as analogs of celecoxib that lacked allelic variants are related to changes in biological func- COX-2 inhibitory activity also exhibited a similar effect on tions in the inflammation pathway. In their study, Landi nematode lifespan, the anti-aging effect of celecoxib might and colleagues observed an association between in- be independent of its COX-2 inhibitory activity. In- creased CRC risk and the C-allele of a SNP −174 G > C deed, celecoxib was shown to inhibit the activity of in the IL-6 gene (Odds ratio (OR) = 1.65, 95 % CI, 0.99– 3’-phosphoinositide-dependent kinase-1 (PDK-1), a 2.74). Several reports showed the association of C-allele key component of the insulin/IGF-1 signaling cascade carriers with inflammatory-related conditions, such as that is involved in lifespan regulation in C. elegans. increased plasma levels of C-reactive protein [36], higher Other studies have demonstrated that NSAIDs have serum levels of IL-6 after coronary artery bypass sur- antioxidative effects through anti-radical activity and gery [37] and asymptomatic carotid artery atheroscler- membrane-stabilizing action [44, 45]. osis [38]. In terms of CRC risk, the effect of alcohol Thus, NSAIDs might be effective for slowing aging drinking was evident only in the subgroup of IL-6 C- and prevention of age-related diseases through not allele carriers (OR = 2.19, 95 % CI, 1.3–3.7), and the only their anti-inflammatory effects via COX-2 use of NSAIDs halved the risk from 2.02 (95 % CI, inhibitory action but through potential secondary 1.38–2.95) to 1.02 (95 % CI, 0.65–1.61) in the carriers of targets including PDK-1 inhibition and the anti- the C-allele. oxidative effect. Hamoya et al. Genes and Environment (2016) 38:6 Page 4 of 7 Triglycerides and NSAIDs treated with aspirin. Aspirin treatment reduced hepatic The triglyceride values (TG, Neutral fat value) are one of NF-κB activity in high-fat diet-fed APOC1 and wild-type the three indices characterizing metabolic syndrome. mice, and in addition, aspirin decreased plasma TG Metabolic syndrome is evoked by an accumulation of levels (−32 %, P < 0.05) in hypertriglyceridemic APOC1 abdominal fat, and, as previously mentioned, several mice. This TG-lowering effect could not be explained by obesity-associated cancers [46] may occur. enhanced VLDL-TG clearance, but aspirin selectively re- The serum TG value is correlated with a high-fat diet duced hepatic production of VLDL-TG in both APOC1 and is higher in patients in an obese state. When the (−28 %, P < 0.05) and wild-type mice (−33 %, P < 0.05) serum TG value increases, colorectal adenomas (often in without affecting VLDL-apoB production [52]. In such as colon polyps) are more likely to occur. This oc- humans, higher proportions of patients in the salsalate currence has been noted in several epidemiological stud- (one of the NSAIDS) treatment groups experienced de- ies. For example, high TGs in hypertriglyceridemia were creasing circulating TG values and increasing adiponec- associated with colorectal adenoma (OR = 1.5, 95 % CI, tin concentrations [53]. For preventing colorectal 1.1–2.0 for the highest versus the lowest quartile, P = carcinogenesis, significant consideration should be given trend 0.03). A stronger association was observed between three to the use of NSAIDs to decrease plasma TG levels. or more adenoma cases and study controls (OR = 2.3, 95 % CI, 1.3–4.2, P < 0.001) [7]. In Japanese men, risk Smoking and NSAIDs trend of CRC is increased under high-TG levels [6]. Animal ex- Smoking is a strong risk factor for the incidence of periments supported the relation between high-TG and colorectal adenomas [7] but a weak risk factor for the carcinogenesis by explaining the underlying mechanisms. colorectal adenocarcinomas [54]. Conversely, NSAIDs Thus, high TG might be understood as a risk factor for including aspirin are known to reduce the adenoma CRC [47, 48]. recurrence rate. Evidence has accumulated that shows On the other hand, there are a variety of discussions current smoking abrogates or inversely affects the use about whether NSAIDs can adjust the TG value. of aspirin. NSAIDs can inhibit the enzymatic activity of COX and We recently performed two trials using enteric-coated attenuate the expression level of PGE . PGE is activated aspirin and found that aspirin similarly increased the 2 2 through an EP3 receptor at the thermoregulatory center risk of colorectal adenomas in current smokers [55]. in the hypothalamus and functions to raise the set point One of these trials is the J-CAPP Study [56]. It is a ran- of body temperature by increasing the cellular metabol- domized controlled trial involving 311 patients from ism. This linkage means NSAIDs decrease TG levels. Asia with colorectal adenomas and/or early-stage adeno- Furthermore, PGE induces the expression of TNFα , and carcinomas (adenocarcinomas with invasions confined the TG value also increases because of the inhibition of to the mucosa) that evaluated the effects of 100 mg/day lipoprotein lipase (LPL) [49]. LPL catalyzes the hydroly- enteric-coated aspirin for two years. In subgroup ana- sis of plasma TG. lyses, we found a reduced adenoma recurrence rate with The lowering of the TG value by NSAIDs is also found an OR of 0.37 (95 % CI, 0.21–0.68) in non-smokers in several studies in the literature. For example, when (never-smokers/ex-smokers) and 3.45 (95 % CI, 1.12– NSAIDs were used in animal experimental models, they 10.64) in current smokers. The other trial is the J-FAPP significantly reduced the total cholesterol, TG and low- Study II [57]. It is also a randomized controlled trial. It density lipoprotein (LDL) concentrations in the plasma involved 34 subjects with Asian familial adenomatous of hyperlipidemic rats [49, 50]. polyposis that evaluated the effects of 100 mg/day Niho et al. investigated the influence of the general enteric-coated aspirin for 6 to 10 months. In the trial, COX inhibitor, indomethacin, in Min mice and found the OR for a reduction in the diameter of polyps was that treatment with 10 ppm indomethacin in the diet for 0.10 (95 % CI, 0.01–0.98) in non-smokers and 3.00 (95 14 weeks caused 90 % reduction in serum TG values, % CI, 0.15–59.89) in current smokers. along with a reduction in the number of intestinal After our findings, two papers confirmed the effects of polyps to 25 % of the untreated control value [51]. In aspirin use on the status of smoking for colorectal aden- this experiment, LPL mRNA levels in the liver were oma recurrence. A randomized, double-blind, placebo- slightly increased by indomethacin treatment. In controlled trial was performed at centers in Europe, humans, indomethacin does not affect serum lipids. Russia, or the US using 75 mg aspirin for 3 years for pa- In another model animal experiment, aspirin could tients with 1 or more sporadic adenomas removed from improve serum high-TG. Human apolipoprotein CI the colon or rectum [58]. Its subgroup analyses revealed (apoCI)-expressing mice (APOC1 mice), an animal OR values of 0.65 (95 % CI, 0.26 − 1.22) and 1.70 (95 % model with elevated plasma TG levels, as well as normo- CI, 0.70–4.09) in non-smokers and current smokers, re- lipidemic wild-type mice, were fed a high-fat diet and spectively. The other paper was a cross-sectional study Hamoya et al. Genes and Environment (2016) 38:6 Page 5 of 7 including 2,918 consecutive colonoscopy patients over a Competing interest The authors declare that they have no competing interests. 30-month period at a university hospital in the US [59]. The incidental rate ratio (IRR) of polyps was 1.72 (95 % Authors’ contributions CI, 1.46–2.02) in active smokers and 0.73 (95 % CI, TH, GF, SM, MT and MM wrote the manuscript. YT conducted the literature review. JT and KW was involved in the critical revision or supervision of the 0.61–0.86) in daily aspirin users compared to those with- manuscript. All authors read and approved the final manuscript. out aspirin. Current smoking interacts significantly with aspirin, resulting in an IRR of 1.69 (95 % CI, 1.28–2.24) Acknowledgements that shows loss of aspirin protection. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant number The mechanism by which smoking influences the ef- 25290049), and also supported by Grants-in-Aid for National Cancer Center fect of aspirin is unknown. One clue is that smoking Research and Development Fund, for the U.S. – Japan Cooperative Medical may be associated with resistance to aspirin, possibly Science Program, from the Ministry of Health, Labor and Welfare of Japan. through excessive thromboxane production [60, 61]. Author details Further studies are warranted because this issue is very Epidemiology and Prevention Division, Research Center for Cancer important for the clinical use of aspirin in the future. Prevention and Screening, National Cancer Center, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan. Department of Biological Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsusika-ku, Tokyo 125-8585, Conclusion with recent recommendation of low- Japan. Division of Carcinogenesis and Cancer Prevention, National Cancer dose aspirin Center Research Institute, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan. Central Animal Division, National Cancer Center Research Institute, 5-1-1 On September 15, 2015, the U.S. Preventive Services TsukijiChuo-ku, Tokyo 104-0045, Japan. Graduate Division of Nutritional and Task Force (USPSTF) posted a draft recommendation Environmental Sciences, University of Shizuoka, 52-1 YadaSuruga-ku, statement with several limitations about taking low-dose Shizuoka 422-8526, Japan. aspirin every day to help prevent cardiovascular disease Received: 24 December 2015 Accepted: 3 February 2016 (CVD), such as heart attack and stroke, and CRC [62]. They stated that patients aged 50–59 who have a 10 % or greater 10-year CVD risk [63] but who are not at in- References 1. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. creased risk for bleeding and have at least a 10-year life Long-term effect of aspirin on colorectal cancer incidence and mortality: expectancy fall within the USPSTF B recommendation 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–50. to take low-dose aspirin daily for at least 10 years. The 2. Komiya M, Fujii G, Takahashi M, Iigo M, Mutoh M. 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Effects of NSAIDs on the risk factors of colorectal cancer: a mini review

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Springer Journals
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Copyright © 2016 by The Author(s)
Subject
Biomedicine; Human Genetics
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1880-7062
DOI
10.1186/s41021-016-0033-0
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27350826
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Abstract

Evidence from epidemiological and experimental studies has shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer (CRC). The function of NSAIDs and the molecular targets for chemopreventive effects on CRC have been extensively studied and their data were reported. However, the relation between NSAIDs and the risk factors of CRC have not been fully elucidated yet. Thus, relations between NSAIDs and the risk factors of CRC, such as overweight and obesity, alcohol, aging, hypertriglyceridemia and smoking, are summarized with our data and with recent reported data in this review. Keywords: Non-steroidal anti-inflammatory drugs, Colorectal cancer, Risk factors, Chemoprevention Background pathway. The constitutive enzyme COX-1 has low ex- Non-steroidal anti-inflammatory drugs (NSAIDs) relieve pression in normal human colorectal tissue, whereas the pain, reduce inflammation, lower fevers and prevent inducible enzyme COX-2 is elevated in tissue involved blood from clotting. Thus, NSAIDs are used to treat in- in inflammation and in cancer. Traditional NSAIDs flammatory conditions such as arthritis. One of the trad- block the actions of both COX-1 and COX-2, and select- itional NSAIDs, aspirin, was used to protect against ive COX-2 inhibitors are a special category of NSAIDs. heart disease. Conversely, NSAIDs can increase the risk In addition, aspirin can inhibit proliferation and induce of gastrointestinal (GI) bleedings/ulcer and interfere with apoptosis of colon cancer cells [2]. The inhibition and kidney function. The severity of side effects increases by induction by aspirin include the following: (i) the inter- taking NSAIDs longer. ruption of nuclear factor kappa B (NF-κB), (ii) the inter- A large number of epidemiological and experimental ruption of extracellular signal-regulated kinases, (iii) the studies have shown that NSAIDs reduce the risk of colo- induction of caspase 8 and 9, and (iv) the inhibition of rectal cancer (CRC). Meta-analysis of randomized trials β-catenin signaling. revealed that use of aspirin for approximately 5 years re- As shown above, the function and molecular targets of duces incidence and mortality due to CRC by 30–40 % NSAIDs have been well studied, and several pieces of after 20 years of follow-up [1]. evidence have shown their chemopreventive effects on The effectiveness of NSAIDS may be attributed to CRC. However, the relation between NSAIDs and the their potent inhibition of cyclooxygenase (COX) en- risk factors of CRC have not been well examined. In this zymes because COX-2 expression and prostaglandin review, such relationships are summarized with our data (PG) E synthesis are elevated in CRC. The COXs/PGH and recent reported data in the text, Table 1 and 2. synthases have two enzymes, COX-1 and COX-2, and COX is the limiting enzyme of the PG synthesis Risk factors of colorectal cancer A risk factor is any attribute, characteristic or exposure * Correspondence: mimutoh@ncc.go.jp 1 of an individual that increases the likelihood of develop- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 TsukijiChuo-ku, ing a disease or injury [3]. In the case of cancer, it is de- Tokyo 104-0045, Japan fined as factors that increase the chance of developing Division of Carcinogenesis and Cancer Prevention, National Cancer Center cancer. Some people with several risk factors never de- Research Institute, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan Full list of author information is available at the end of the article velop cancer. There is an intensity of correlation © 2016 Hamoya et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hamoya et al. Genes and Environment (2016) 38:6 Page 2 of 7 Table 1 Effects of NSAIDs on risk factors of CRC cause chronic low-grade inflammatory states, increased proliferation and angiogenesis, and promote colon car- Risk factors of CRC NSAIDs effects on each factors cinogenesis [12, 13]. Obesity Lose weight and reduce the BMI The use of NSAIDs is associated with reduced risk of Alcohol Increasing risk of GI bleeding due to alcohol inflammation-associated cancers, and obesity-related Aging Slowing cancers are included in inflammation-related cancers Hypertriglyceridemia Improvement [14]. Compared with non-users of NSAIDs, lower risk of Smoking ー obesity-related cancers in NSAID users (hazard ratio BMI body mass index, CRC colorectal cancer, GI gastrointestinal (HR) = 0.88; 95 % confidence interval (CI), 0.85–0.92) NSAIDs Non-steroidal anti-inflammatory drugs has been reported [14]. Although the preventive effects of aspirin and NSAIDs on obesity-related cancers are in- between risk factors and cancer. Thus, there might be conclusive, there are several reports showing that aspirin some weak risk factors of which we are not aware. reduced risks of obesity-related cancers including CRC, Several risk factors of CRC have been demonstrated to particularly among obese people. In the Aspirin/Folate date. The World Health Organization (WHO) lists fac- Polyp Prevention Study, a randomized controlled trial of tors that are convincing evidence for the risk of CRC in aspirin and folic acid to prevent colorectal adenoma, a daily life as follows: (i) consuming red meat, (ii) consum- daily dose of 325 mg aspirin reduced the risk ratio for ing processed meat, (iii) alcoholic drinks (men), (iv) body advanced adenomas compared with placebo among fatness / abdominal fatness, and (v) adult attained height obese subjects (relative risk (RR) = 0.44; 95 % CI, 0.17– increase [4]. Other risk factors are reported as aging [5] 1.10) but not among those with normal weight (RR = and a family history of CRC. Several medical histories of 1.23; 95 % CI, 0.55–2.77) [15]. In the CAPP2 study that diseases are known to increase the risk of CRC, such as recruited participants with Lynch syndrome, CRC risk (i) genetic predisposition including familial adenomatous was 2.41x greater for obese participants (95 % CI, polyposis and hereditary nonpolyposis CRC, (ii) high- 1.06–2.96; P = 0.03) than for underweight and normal- risk adenoma, (iii) inflammatory bowel disease, (iv) type- weight participants, and the obesity-related excess risk 2 diabetes, and (v) hypertriglyceridemia [6]. Moreover, of CRC was confined to those randomly assigned to smoking is a strong factor in the development of colo- the aspirin placebo group (adjusted HR = 2.75; 95 % rectal adenoma [7]. CI, 1.12–6.79, P = 0.03), but the risk was abrogated in From recent published literature, we took particular those taking aspirin [16]. note of overweight and obesity, alcohol, aging, hypertri- PGE levels in rectal mucosa have been reported to be glyceridemia and smoking. The relation between each positively associated with BMI [17]. PGE has been shown risk factor and NSAIDs is described below. to promote colorectal carcinogenesis [18] and metastasis [19] in mouse models, and inhibition of PGE synthesis is Obesity and NSAIDs a potential target for prevention of CRC [20]. Therefore, Obesity is an important risk factor for CRC [8], and decrease of obesity-related CRC by NSAID use could be there is a significant positive correlation between body due to inhibition of PGE production. mass index (BMI) and CRC risk [9, 10]. Visceral abdom- Obesity causes insulin resistance with hyperglycemia inal fat area measured by CT scan is more significantly and hyperinsulinemia, and these contribute to tumor de- associated with colorectal adenoma [11]. Visceral fat ac- velopment [21]. Metformin, an insulin resistance- cumulation causes increases in adipokines such as leptin, improving, anti-diabetic agent, has been reported to re- inflammatory cytokines such as tumor necrosis factor duce risks of various cancers including colon cancer in (TNF) α and interleukin (IL)-6, and growth factors such diabetic and non-diabetic populations [22, 23]. Metformin as insulin-like growth factor (IGF)-I and vascular endo- inhibits cell proliferation via activation of AMP-activated thelial growth factor (VEGF) [12, 13]. These factors protein kinase (AMPK) [24]. Serum adiponectin is de- creased in obese people, and also activates AMPK and in- hibits cell proliferation of colon cancer cells [24]. Recently, Table 2 Effects of NSAIDs plus each risk factors on CRC risk it has been reported that aspirin activates AMPK and in- Risk factors of CRC NSAIDs effects on CRC risk hibits mTOR signaling in colon cancer cells [25]. Not all, Obesity Decreasing [14–16] but several NSAIDs, such as salicylic acid, ibuprofen or Alcohol Protection in a social drinker diclofenac, which have acidic structures, also induce Aging ー AMPK activation [26, 27]. This effect is considered to be a Hypertriglyceridemia Decreasing [49, 50] COX-independent anti-inflammatory property of aspirin Smoking Increasing [57–59] and a subgroup of NSAIDs and may contribute to de- CRC colorectal cancer, NSAIDs Non-steroidal anti-inflammatory drugs crease obesity-related cancer risks. Hamoya et al. Genes and Environment (2016) 38:6 Page 3 of 7 Alcohol and NSAIDs These reports suggest that the carcinogenic effect of In a meta-analysis of cohort and case–control studies, alcohol may be partly through the induction of acetal- there are reports describing moderately increased risks dehyde and inflammation, and NSAID use may effect- of CRC with a dose–response relation for rising alcohol ively protect CRC development in a social drinker. consumption. A polled analysis of eight cohort studies also recorded a dose–response relation between the risk of CRC and the amount of alcohol consumption [28]. Aging and NSAIDs The mechanisms by which alcohol intake exerts its Disruption of normal tissue function dramatically accel- carcinogenic effect are not fully understood yet. Acetal- erates in old age. Aging is the greatest risk factor for dehyde, a metabolite of alcohol, is implicated in esopha- numerous pathologies, including cancer, stroke, neuro- geal carcinogenesis but is not strongly implicated in degenerative disorders, heart disease and type-2 diabetes colorectal carcinogenesis. Recently, single nucleotide [5]. Chronic inflammation is one of the main processes polymorphisms (SNPs) in the alcohol dehydrogenase, that contributes to age-related disease and causes dis- ADH1B, and aldehyde dehydrogenase, ALDH2, of mod- ruption of normal functioning of tissues. Notably, there erate/heavy drinkers were shown to be contributing fac- is a robust increase of mRNA and secretion of numerous tors for CRC [29]. Aspirin and salicylate could inhibit cytokines, chemokines, growth factors and proteases in both human ADH (metabolize ethanol to acetaldehyde) the senescent cells, and these cells may cause a low level and ALDH (degradation of acetaldehyde) activities [30]. of chronic inflammation systemically during aging [39]. To date, the effect of aspirin on acetaldehyde production Yeast, nematodes and flies have been recognized as ex- is not fully understood yet. cellent model systems for studying the underlying mech- Ethanol is known as an irritant for the digestive tract. anism of aging and identifying chemicals altering Ethanol intake is known to be an independent risk factor longevity, mainly because of their short lifespans. A grow- for GI bleeding. It is posited that the GI bleeding risk ing number of reports showed the effects of NSAIDs on from aspirin is high in individuals who consume three the lifespan extension in yeast [40], nematodes [40, 41], or more alcoholic drinks every day [31]. flies [40, 42] and mice [43]. He et al. [40] reported that Several reports suggest that ethanol exposure alters the ibuprofen extended the replicative life span of Saccharo- cytokine levels and inflammatory status in a variety of tis- myces cerevisiae cells by destabilizing the high-affinity sues in vitro and in vivo, including the colon [32, 33]. Fur- tryptophan transporter. He et al. also found that ibuprofen thermore, chronic alcohol intake promoted intestinal caused small size at birth and moderate delay in initiation Min/+ tumorigenesis and tumor invasion in Apc mice [34]. of cell division, which was observed in most long-lived In a report, Wimberly et al. suggested that mast cell- yeast mutants. Meanwhile, celecoxib extended both mean mediated inflammation could be one of the mechanisms and maximum lifespans in C. elegans [41]. The physical by which alcohol promotes intestinal carcinogenesis. health, as indicated by the age-associated decay rate of Recently, Landi and colleagues [35] studied the associ- motor activity, was also significantly improved in ation between SNPs in the IL-6, IL-8, TNFα and PPARG celecoxib-treated nematodes without affecting the nutri- genes and the risk of CRC by a hospital-based case con- tional value. However, no homologs of mammalian COXs trol study. These genes are known to play important have been identified in unicellular organisms, including C. roles in inflammation of the colorectum, and common elegans. Furthermore, as analogs of celecoxib that lacked allelic variants are related to changes in biological func- COX-2 inhibitory activity also exhibited a similar effect on tions in the inflammation pathway. In their study, Landi nematode lifespan, the anti-aging effect of celecoxib might and colleagues observed an association between in- be independent of its COX-2 inhibitory activity. In- creased CRC risk and the C-allele of a SNP −174 G > C deed, celecoxib was shown to inhibit the activity of in the IL-6 gene (Odds ratio (OR) = 1.65, 95 % CI, 0.99– 3’-phosphoinositide-dependent kinase-1 (PDK-1), a 2.74). Several reports showed the association of C-allele key component of the insulin/IGF-1 signaling cascade carriers with inflammatory-related conditions, such as that is involved in lifespan regulation in C. elegans. increased plasma levels of C-reactive protein [36], higher Other studies have demonstrated that NSAIDs have serum levels of IL-6 after coronary artery bypass sur- antioxidative effects through anti-radical activity and gery [37] and asymptomatic carotid artery atheroscler- membrane-stabilizing action [44, 45]. osis [38]. In terms of CRC risk, the effect of alcohol Thus, NSAIDs might be effective for slowing aging drinking was evident only in the subgroup of IL-6 C- and prevention of age-related diseases through not allele carriers (OR = 2.19, 95 % CI, 1.3–3.7), and the only their anti-inflammatory effects via COX-2 use of NSAIDs halved the risk from 2.02 (95 % CI, inhibitory action but through potential secondary 1.38–2.95) to 1.02 (95 % CI, 0.65–1.61) in the carriers of targets including PDK-1 inhibition and the anti- the C-allele. oxidative effect. Hamoya et al. Genes and Environment (2016) 38:6 Page 4 of 7 Triglycerides and NSAIDs treated with aspirin. Aspirin treatment reduced hepatic The triglyceride values (TG, Neutral fat value) are one of NF-κB activity in high-fat diet-fed APOC1 and wild-type the three indices characterizing metabolic syndrome. mice, and in addition, aspirin decreased plasma TG Metabolic syndrome is evoked by an accumulation of levels (−32 %, P < 0.05) in hypertriglyceridemic APOC1 abdominal fat, and, as previously mentioned, several mice. This TG-lowering effect could not be explained by obesity-associated cancers [46] may occur. enhanced VLDL-TG clearance, but aspirin selectively re- The serum TG value is correlated with a high-fat diet duced hepatic production of VLDL-TG in both APOC1 and is higher in patients in an obese state. When the (−28 %, P < 0.05) and wild-type mice (−33 %, P < 0.05) serum TG value increases, colorectal adenomas (often in without affecting VLDL-apoB production [52]. In such as colon polyps) are more likely to occur. This oc- humans, higher proportions of patients in the salsalate currence has been noted in several epidemiological stud- (one of the NSAIDS) treatment groups experienced de- ies. For example, high TGs in hypertriglyceridemia were creasing circulating TG values and increasing adiponec- associated with colorectal adenoma (OR = 1.5, 95 % CI, tin concentrations [53]. For preventing colorectal 1.1–2.0 for the highest versus the lowest quartile, P = carcinogenesis, significant consideration should be given trend 0.03). A stronger association was observed between three to the use of NSAIDs to decrease plasma TG levels. or more adenoma cases and study controls (OR = 2.3, 95 % CI, 1.3–4.2, P < 0.001) [7]. In Japanese men, risk Smoking and NSAIDs trend of CRC is increased under high-TG levels [6]. Animal ex- Smoking is a strong risk factor for the incidence of periments supported the relation between high-TG and colorectal adenomas [7] but a weak risk factor for the carcinogenesis by explaining the underlying mechanisms. colorectal adenocarcinomas [54]. Conversely, NSAIDs Thus, high TG might be understood as a risk factor for including aspirin are known to reduce the adenoma CRC [47, 48]. recurrence rate. Evidence has accumulated that shows On the other hand, there are a variety of discussions current smoking abrogates or inversely affects the use about whether NSAIDs can adjust the TG value. of aspirin. NSAIDs can inhibit the enzymatic activity of COX and We recently performed two trials using enteric-coated attenuate the expression level of PGE . PGE is activated aspirin and found that aspirin similarly increased the 2 2 through an EP3 receptor at the thermoregulatory center risk of colorectal adenomas in current smokers [55]. in the hypothalamus and functions to raise the set point One of these trials is the J-CAPP Study [56]. It is a ran- of body temperature by increasing the cellular metabol- domized controlled trial involving 311 patients from ism. This linkage means NSAIDs decrease TG levels. Asia with colorectal adenomas and/or early-stage adeno- Furthermore, PGE induces the expression of TNFα , and carcinomas (adenocarcinomas with invasions confined the TG value also increases because of the inhibition of to the mucosa) that evaluated the effects of 100 mg/day lipoprotein lipase (LPL) [49]. LPL catalyzes the hydroly- enteric-coated aspirin for two years. In subgroup ana- sis of plasma TG. lyses, we found a reduced adenoma recurrence rate with The lowering of the TG value by NSAIDs is also found an OR of 0.37 (95 % CI, 0.21–0.68) in non-smokers in several studies in the literature. For example, when (never-smokers/ex-smokers) and 3.45 (95 % CI, 1.12– NSAIDs were used in animal experimental models, they 10.64) in current smokers. The other trial is the J-FAPP significantly reduced the total cholesterol, TG and low- Study II [57]. It is also a randomized controlled trial. It density lipoprotein (LDL) concentrations in the plasma involved 34 subjects with Asian familial adenomatous of hyperlipidemic rats [49, 50]. polyposis that evaluated the effects of 100 mg/day Niho et al. investigated the influence of the general enteric-coated aspirin for 6 to 10 months. In the trial, COX inhibitor, indomethacin, in Min mice and found the OR for a reduction in the diameter of polyps was that treatment with 10 ppm indomethacin in the diet for 0.10 (95 % CI, 0.01–0.98) in non-smokers and 3.00 (95 14 weeks caused 90 % reduction in serum TG values, % CI, 0.15–59.89) in current smokers. along with a reduction in the number of intestinal After our findings, two papers confirmed the effects of polyps to 25 % of the untreated control value [51]. In aspirin use on the status of smoking for colorectal aden- this experiment, LPL mRNA levels in the liver were oma recurrence. A randomized, double-blind, placebo- slightly increased by indomethacin treatment. In controlled trial was performed at centers in Europe, humans, indomethacin does not affect serum lipids. Russia, or the US using 75 mg aspirin for 3 years for pa- In another model animal experiment, aspirin could tients with 1 or more sporadic adenomas removed from improve serum high-TG. Human apolipoprotein CI the colon or rectum [58]. Its subgroup analyses revealed (apoCI)-expressing mice (APOC1 mice), an animal OR values of 0.65 (95 % CI, 0.26 − 1.22) and 1.70 (95 % model with elevated plasma TG levels, as well as normo- CI, 0.70–4.09) in non-smokers and current smokers, re- lipidemic wild-type mice, were fed a high-fat diet and spectively. The other paper was a cross-sectional study Hamoya et al. Genes and Environment (2016) 38:6 Page 5 of 7 including 2,918 consecutive colonoscopy patients over a Competing interest The authors declare that they have no competing interests. 30-month period at a university hospital in the US [59]. The incidental rate ratio (IRR) of polyps was 1.72 (95 % Authors’ contributions CI, 1.46–2.02) in active smokers and 0.73 (95 % CI, TH, GF, SM, MT and MM wrote the manuscript. YT conducted the literature review. JT and KW was involved in the critical revision or supervision of the 0.61–0.86) in daily aspirin users compared to those with- manuscript. All authors read and approved the final manuscript. out aspirin. Current smoking interacts significantly with aspirin, resulting in an IRR of 1.69 (95 % CI, 1.28–2.24) Acknowledgements that shows loss of aspirin protection. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant number The mechanism by which smoking influences the ef- 25290049), and also supported by Grants-in-Aid for National Cancer Center fect of aspirin is unknown. One clue is that smoking Research and Development Fund, for the U.S. – Japan Cooperative Medical may be associated with resistance to aspirin, possibly Science Program, from the Ministry of Health, Labor and Welfare of Japan. through excessive thromboxane production [60, 61]. Author details Further studies are warranted because this issue is very Epidemiology and Prevention Division, Research Center for Cancer important for the clinical use of aspirin in the future. Prevention and Screening, National Cancer Center, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan. Department of Biological Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsusika-ku, Tokyo 125-8585, Conclusion with recent recommendation of low- Japan. Division of Carcinogenesis and Cancer Prevention, National Cancer dose aspirin Center Research Institute, 5-1-1 TsukijiChuo-ku, Tokyo 104-0045, Japan. Central Animal Division, National Cancer Center Research Institute, 5-1-1 On September 15, 2015, the U.S. Preventive Services TsukijiChuo-ku, Tokyo 104-0045, Japan. Graduate Division of Nutritional and Task Force (USPSTF) posted a draft recommendation Environmental Sciences, University of Shizuoka, 52-1 YadaSuruga-ku, statement with several limitations about taking low-dose Shizuoka 422-8526, Japan. aspirin every day to help prevent cardiovascular disease Received: 24 December 2015 Accepted: 3 February 2016 (CVD), such as heart attack and stroke, and CRC [62]. They stated that patients aged 50–59 who have a 10 % or greater 10-year CVD risk [63] but who are not at in- References 1. Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. creased risk for bleeding and have at least a 10-year life Long-term effect of aspirin on colorectal cancer incidence and mortality: expectancy fall within the USPSTF B recommendation 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–50. to take low-dose aspirin daily for at least 10 years. The 2. Komiya M, Fujii G, Takahashi M, Iigo M, Mutoh M. 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