Concept of chemoprevention in colorectal cancer

Abstract

Colorectal cancer remains a significant cause of morbidity and mortality throughout the world. The incidence of colorectal cancer is nearly four-fold higher in more-developed as compared with less-developed regions of the world. At present an early detection of colorectal cancer remains a crucial step in determining the therapeutic outcomes. Screening programmes have been introduced in an effort to detect colorectal cancer at an early stage or at a precancerous colonic polyp stage. These programmes should be used by the health professionals as an opportunity to educate the public regarding the use of chemoprevention in colorectal cancer, which is the main focus of this review and an attractive concept needing further evaluation.

Key Words: Colorectal cancer, Chemoprevention, Geographical variations, Dietary carcinogens

INTRODUCTION

Colorectal cancer (CRC) is one of the most common cancers worldwide leading to significant mortality and morbidity[1]. Colorectal cancer incidence rates both among men and women are nearly fourfold higher in more-developed as compared with less-developed regions of the world[1]. The reasons for this variability in CRC prevalence in different geographical areas are not fully known. This however has been studied extensively and the role of various carcinogenic factors has been the target of clinical, experimental, and epidemiological studies. Most studies favour an aetiological role of dietary, lifestyle, and genetic factors in CRC, however, some studies have demonstrated equivocal or even negative results. These observations have been analysed in detail in a recent review[2].

Colorectal screening programmes are an excellent opportunity to educate the public regarding the carcinogenic potential of dietary and lifestyle factors. Current emphasis of most CRC screening programmes is to detect cancer at an early, or preferably at a precancerous-stage of colonic polyps. This approach maximises survival outcomes. Modifications of carcinogenic factors coupled with chemoprevention are important targets for the future approach to CRC prevention. We will focus on the role of chemoprevention in this review, while giving brief description of lifestyle and dietary factors.

CHEMOPREVENTION IN COLORECTAL CANCER

Observations from earlier experimental studies suggested a protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of tumour growth[3,4]. Such experimental data was supported from epidemiological studies which showed significant nonspecific tumour risk reduction of between 20%-50% among NSAID users[5-7]. A consistent beneficial effect of aspirin and NSAIDs in reducing formation of colonic polyps was also reported in a systemic review[8].

Cancer chemopreventive mechanisms for NSAIDs

It is suggested that colorectal carcinoma risk reduction from NSAIDs is mainly related with inhibition of cyclooxygenase (COX), particularly COX-2, which is raised in colorectal neoplasia[9]. Other effects of aspirin on the oncogenic Wnt/β-catenin pathway activity in colorectal cancer cell lines have been studied. For example a dose-dependent decreased activity of this pathway, as judged by TCF-driven luciferase activity, reduced Wnt target gene expression and increased phosphorylation of β-catenin by immunoblotting[10] has been demonstrated. In this study, ubiquitination and cytoplasmic levels of β-catenin were assessed by immunoblotting, and the localization of β-catenin was shown by green fluorescent protein-tagged β-catenin and time-lapse fluorescent imaging. Interestingly, aspirin treatment caused increased phosphorylation of protein phosphatase 2A (PP2A), an event associated with inhibition of PP2A enzymatic activity. This was confirmed by a reduction in enzymatic PP2A activity. Moreover, this inhibition of PP2A enzymatic activity appeared essential for the effects of aspirin on the Wnt/β-catenin pathway as shown by transient transfection with PP2A constructs. The findings in this trial provided a molecular explanation for the efficacy of aspirin in chemoprevention of colorectal cancer and showed biochemical evidence that PP2A had an important regulatory effect on Wnt/β-catenin pathway activity in these cells.

Chemopreventive agents and outcomes

In various trials where aspirin and NSAIDs were used as chemoprotective agents, a higher dose had favourable results, however findings were inconsistent[5,11,12]. In general the regular use of aspirin appears to reduce the incidence of colorectal adenoma with relative risk reductions on the order of 13% to 28% in average-risk individuals as shown in Table 1[13-27]. On the basis of a limited number of studies, the relative risk reductions for individuals with a history of colonic adenoma are probably higher than for those at average risk. Furthermore, it appears that longer duration of aspirin use, as well as higher doses, are associated with greater relative risk reductions than smaller doses and shorter duration as shown in Table 2[28-33]. A randomised, placebo-controlled trial included 2586 patients with a recent history of adenoma[34]. These patients were assigned to receive either placebo or selective COX-2 inhibitor (rofecoxib 25 mg/d) with results showing significant reduction in adenoma recurrence (P < 0.0001) in experimental group. However, in the rofecoxib group a significantly higher rate of upper gastrointestinal and thrombotic cardiovascular event were observed. With this initial and subsequent reporting of significant cardiovascular events, use of COX-2 inhibitors as a chemopreventive agent has largely been discontinued[34,35].

Table 1 Use of aspirin in average risk subjects and colonic neoplasia risk reduction.

Study	n	Aspirin dose (mg/AD)	Study duration (yr)	Relative risk reduction (95% CI)
Thun et al[13]	622 424	100 mg3	≥ 1	0.58 (0.36-0.93)1
				0.61 (0.38-0.97)2
Gann et al[14]	22071	325	5	1.15 (0.80-1.65)1
Cook et al[15]	39876	100	10	0.97 (0.77-1.24)2
Stürmer et al[16]	22071	325	12	1.03 (0.83-1.28)
Giovannucci et al[17]	47900	325	4	0.54 (0.34-0.84)1
Paganini-Hill et al[18]	13979	325	7-10	1.38 (NR)1
Chan et al[19]	89446	100	10	0.62 (0.44-0.86)2
Friis et al[20]	29470	325	6	0.9 (0.70-1.10)1
García-Rodríguez et al[21]	12005	325	> 2	0.9 (0.8-1.1)
Reeves et al[22]	845	100	> 5	0.79 (0.46-1.36)2
Juarranz et al[23]	502	325	NR	0.32 (0.09-1.10)
La Vecchia et al[24]	3248	325	5	0.7 (0.50-1.00)
Kune et al[25]	1442	325	NR	0.57 (0.41-0.79)
Suh et al[26]	2704	325	6	0.33 (0.15-0.72)
Slattery et al[27]	3051	325	> 5	0.7 (0.6-0.8)

¹Males;

²Females;

³Daily; AD: Alternate day dosage; CI: Confidence interval; NR: Not reported.

Table 2 Role of aspirin in colorectal neoplasia risk among patients with past tumour.

Trials	n	Aspirin dose	Duration (yr)	Relative risk (95% CI)
Baron et al[28]	1121	81/325 mg	1	0.96 (0.81-1.13)
Benamouzig et al[29]	272	160/300 mg	1	0.82 (0.7-0.95)
Greenberg et al[30]	864		4	0.52 (0.31-0.89)
PPSG[31]	1905	< 325 mg	4	0.82 (0.65-1.02)
		> 325 mg		0.54 (0.3-0.96)
Sandler et al[32]	492	> 15 tab/month	5	0.84 (0.5-1.43)
Breuer-Katschinski et al[33]	442	> 4 tab/week	< 5	0.91 (0.32-2.64)
			> 5	0.09 (0.01-0.82)

CI: Confidence interval; PPSG: Polyp prevention study group.

5-aminosalicylates (ASA) in colorectal cancer prevention

Chemopreventive role of 5-ASA in colorectal carcinoma has been proposed in patients with inflammatory bowel disease. The effect of 5-ASA on the Wnt/β-catenin pathway has been studied in colorectal cancer cell lines to find a molecular basis underlying its chemopreventive features[36]. 5-ASA targets the Wnt/β-catenin pathway in adenomatous polyposis coli mutated cells with intact β-catenin, judged by luciferase reporter assays. In addition, 5-ASA treatment leads to reduced expression of nuclear β-catenin and Wnt/β-catenin target genes, and increased β-catenin phosphorylation. Such effects on the Wnt/β-catenin pathway are mediated via protein phosphatase 2A (PP2A) and increased phosphorylation of PP2A after 5-ASA treatment coincides with decreased PP2A enzymatic activity. The inhibition of PP2A enzymatic activity by 5-ASA appears to be essential for its effect on the Wnt/β-catenin pathway, as shown by transient transfection with siPP2A and mutant PP2A. These effects of 5-ASA are observed in similar doses as used in the treatment of inflammatory bowel disease.

LIFESTYLE AND DIETARY FACTORS

Lifestyle and dietary constituents including fibre content and its source, protein and fat types and their origin, and their consumption patterns vary enormously in different geographical areas and had been linked to CRC aetiology. The potential role of various dietary factors in CRC carcinogenesis and possible preventive strategies are given in Table 3.

Table 3 Colorectal cancer and the potential carcinogenic role of various factors.

CRC category (% diagnosed with CRC)	Intervention strategies
Sporadic CRC (75%)	Screening Programmes
	Detection and removal of polyps (age > 50 yr)
	Role of chemoprevention
	NSAIDs/Aspirin
	5-aminosalicylate
	Dietary and lifestyle factors
	Good: low protein, high fibre, low fat, micronutrients, exercise
	Bad: alcohol, tobacco, obesity
Familial syndromes + miscellaneous (25%)	Screening colonoscopy
	Other: Aspirin and NSAIDs, 5-ASA

CRC: Colorectal cancer; NSAIDs: Non steroidal anti-inflammatory drugs; 5-ASA: 5-aminosalicylates; IBD: Inflammatory bowel disease.

The cancer protective role of fibre has been attributed to its bulking effect, faecal dilution factor, shortening of faecal transit time and fermentation properties. Fibre fermentation products have been studied extensively and among the various products, butyrate a naturally occurring fatty acid was found to be most relevant. Butyrate has a potential to inhibit cell proliferation, induce apoptosis and differentiation, and increase phase II enzyme activities in tumour cells, whereas little information is available on its protective effect in less-transformed colon cells[37,38]. Butyrate from wheat bran leads to higher concentrations in distal large bowel and is more protective compared to butyrate from guar gum and oat bran[39].

The role of fat components depends on the fatty acid composition of food. Thus docosahexaenoic acid which is rich in certain fish may have a role through inhibition of the arachidonic acid cascade involved in carcinogenesis and cell proliferation[40]. The higher prevalence of colon cancer in South Africans whites (17:100 000) was investigated by estimating epithelial proliferation differences in the black Africans (cancer prevalence 1:100 000) based on dietary differences[41]. The lower prevalence of CRC in Mediterranean countries may be related to the use of extra virgin olive oil.

Pinoresinol-rich extra virgin olive oil extracts have potent chemopreventive properties and specifically upregulate the ATM-p53 cascade[42].

Data in relation to the use of red meat and a higher risk of colorectal cancer is relatively consistent, although controversies do exit[43-45]. The proposed mechanisms involved in CRC carcinogenesis and meat consumption relate to intake of a higher quantity of red meat (> 120 g/d), formation of heterocyclic amines, polycyclic aromatic hydrocarbons (dependent on cooking methods) and nitrates, N-Nitroso compound formation, and heme component[46-52].

A higher risk of CRC was suggested from a review of ecological studies which analysed meat consumption patterns among the included populations[53]. Three meta-analyses which included 15 prospective studies on red meat, 14 prospective studies on processed meat, 18 case-control studies and 19 cohorts showed colorectal cancer risk with meat consumption[54-56].

Certain lifestyle factors have been implicated in CRC carcinogenesis, including smoking, alcohol consumption, exercise lack, obesity, and genetics. Factors involved in DNA methylation, synthesis, and repair and factors with antioxidant properties may be involved in colorectal cancer risk which in turn may be influenced by other factors. In a large European cohort, both lifetime and baseline alcohol consumption showed increased colon and rectal cancer risk, with apparent risk being higher for alcohol intake greater than 30 g/d[56]. In another large prospective European multicenter study 368 277 subjects were evaluated using various anthropometric measurements, which found body weight and body mass index to be associated with a significantly higher risk of colon cancer[57]. An Austrian population-based study found an inverse association of weight loss to colorectal carcinoma while adjusting for smoking, occupational group, blood glucose, and body mass index at baseline in over 65 000 subjects[58]. Consumption of micronutrients including vitamin B6, folate, calcium, selenium, caffeine has also been studied in CRC carcinogenesis with mainly controversial results[59,60].

CONCLUSION

Colorectal cancer is an important health issue particularly in the affluent countries. Chemoprevention is an attractive concept in colorectal cancer prevention. This however should be coupled with modification of other lifestyle and dietary factors which have important carcinogenic potential as evident from the current clinical, experimental, and epidemiological studies. We recommend that health professionals should promote public awareness regarding the aetiological role of the modifiable factors alongside the primary prevention using CRC screening programmes. Chemoprevention in the form of NSAIDs and 5-aminosalicylates has a significant role in individuals particularly those with genetic and other CRC predispositions.