Download - University of East Anglia

Colon cancer - a civilization disorder
Alastair J.M. Watson1, Paul D. Collins2
1School
of Medicine, Health Policy and Practice, Faculty of Health, University of East
Anglia
2Division
of Gastroenterology, School of Clinical Sciences, University of Liverpool
*Address for correspondence
Professor Alastair Watson
School of Medicine, Health Policy and Practice
Faculty of Health
University of East Anglia
Norwich NR4 7TJ
Tel: +44 (0) 1603 5907266
Email: [email protected]
Abstract
Colorectal cancer arises in individuals with acquired or inherited genetic
predisposition who are exposed to a range of risk factors. Many of these risk factors
are associated with affluent western societies. More than 95% of colorectal cancers
are sporadic arising in individuals without a significant hereditary risk.
Geographic variation in the incidence of colorectal cancer is considerable with a
higher incidence observed in the West. Environmental factors contribute
substantially to this variation. A number of these risk factors are associated with a
Western lifestyle and could be considered a product of “civilization”. Recently,
smoking has been recognized as a risk factor. Energy consumption also influences
colorectal cancer risk with obesity increasing risk and exercise reducing risk.
However, the strongest contribution to environmental risk for colorectal cancer is
dietary. Consumption of fat, alcohol and red meat is associated with an increased
risk. Fresh fruit and vegetables and dietary fibre may be protective.
Much has been learnt recently about the molecular pathogenesis of colorectal
cancer. Colorectal cancer always arises in the context of genomic instability. There is
inactivation of the tumour suppressor genes APC, p53, TGF-, activation of oncogene
pathways including K-ras and activation of the cyclo-oxygenase-2, Epidermal Growth
Factor Receptor and Vascular Endothelial Growth Factor pathways. The mechanisms
by which some environmental factors modify the mutation risk in these pathways
have been described.
INTRODUCTION
Colorectal cancer is the fourth most common cancer among men and the third most
common cancer among women worldwide. However, the incidence of colorectal
cancer has marked geographical variation with a 25-fold difference in incidence of
colorectal cancer between regions with the lowest rate (Middle Africa; 2.3 per 100
000) and those with the highest rate (Japan; 49.3 per 100 000).1
When countries are divided according to economic development, two-thirds of all
colorectal cancers are found to occur in developed countries.2 It is known that
colorectal cancer develops in individuals with acquired or inherited genetic
predisposition in response to exposure to environmental risk factors. It is the latter,
modifiable risk factors that are thought to contribute substantially to the variation in
incidence.
Epidemiology: Civilization and colorectal cancer incidence
Economic development is characterized by the advancement of agriculture and trade
with progressive urbanization of the population. Civilized societies tend to be
defined as those that have achieved an advanced level of this social progression.
Such development in the West has been associated with a number of changes in
lifestyle factors. Dietary changes have included an increased consumption of meat,
dairy products and processed foods. Other lifestyle changes have included a
reduction in physical activity and an increase in smoking and alcohol consumption. 3;4
These changes have coincided with an increase in a number of diseases include
coronary artery disease, hypertension, asthma, and some cancers including
colorectal cancer, breast cancer and lung cancer.3;5 It has also been observed that
migrants to developed countries tend to acquire the higher risk of cancer of their
host country.3 Further, the rates for second generation migrants can be double that
of the first.6 It may be reasonable, therefore, to describe these diseases, including
colorectal cancer, as diseases of civilization in which a number of acquired risk
factors associated with civilization are implicated. Modification of lifestyle and
dietary factors may be expected to reduce the risk of colorectal cancer and it has
been estimated that up to 50% of cancer could be prevented through the
modification of lifestyle factors alone.7
It has recently been observed that the high incidence rate of colorectal cancer in
high-income countries has stabilised, but that within developing countries,
increasing levels of urbanisation have coincided with a dramatic increase in
incidence of colorectal cancer.8;9 The International Agency for Research on Cancer
(IARC) has collated incidence data from populations from which high quality data are
available. In 27 of 51 cancer registries, colorectal cancer rates increased significantly
from the period 1983-87 to 1998-2002.9 These increases have largely been limited to
countries undergoing economic transition (Eastern European countries, Asia, some
countries in South America). In the United States, colorectal cancer rates declined
during the same period. Worldwide, a smaller increase in the rate of colorectal
cancer has been in observed in women compared to men and it has been proposed
that this may reflect a slower adoption of risk behaviour amongst women.
The most dramatic increase in colorectal cancer incidence has been observed in
Japan, a developed nation with a strong economy. In the last four decades, two of
three registries recorded an increased incidence of colorectal cancer of more than
90%.9 During this period, there has been a Westernization of the Japanese diet with
an increased intake of dairy products, fat and meat.10;11 It has been speculated that
this may account for the major shift in colorectal cancer incidence.
Pathophysiology
Observational studies reporting associations between dietary and lifestyle factors
and the development of colorectal cancer highlight important potential risk factors,
but provide insufficient information to establish causation. Attempts have therefore
been made to provide biologically plausible, mechanistic explanations to understand
how acquired risk factors could influence the mutation risk or the expression of
these molecular pathways. Many of these studies have focused on in vitro or animal
models of colorectal cancer, but some provide information from human studies that
lend support to causative explanations for described associations.
Colorectal cancer arises as a consequence of genomic instability with an
accumulation of genetic errors resulting in dysregulation of molecular pathways
controlling cell migration, differentiation, apoptosis and proliferation.12
Chromosomal instability is the most common pathway by which colorectal cancer
develops and is present in 65-70% of cancers. It is characterized by loss or gains of
whole or large portions of chromosomes.13 Inactivation of the tumour suppressor
gene, adenomatous polyposis coli (APC) is an early initiating event. Activating
mutations in of the K-ras oncogene follow. Additional mutations, including
mutations in transforming growth factor-β (TGF-β) and p53, drive subsequent
malignant transformation,.13 The temporal acquisition of these genetic changes is
matched by the progression from normal colonic epithelium to adenoma formation
and subsequently colorectal cancer.
Up to 15% of all colorectal cancers harbour DNA microsatellite instability arising as a
consequence of loss of DNA mismatch repair activity.14 80% of cancers harbouring
MSI are sporadic with hypermethylation of the promoter region of the mismatch
repair gene MLH-1. The remainder occur as part of the Lynch syndrome (Hereditary
Non-Polyposis Colorectal Cancer (HNPCC)). Tumours with MSI tend to arise in the
proximal colon and have a slightly better prognosis than tumours without MSI.15
The mechanism whereby lifestyle factors may interact with the expression of the
above molecular pathways is explored in more detail below.
Lifestyle factors and development of colorectal cancer
Physical activity, obesity, diet, smoking and alcohol intake have been associated with
development of colorectal cancer. The quality of observational data is variable and
in some cases, contradictory.
Physical activity
People in Western societies have reduced physical activity compared with the rest of
the world and this has been identified as a poor determinant of health.16 Migration
to Western societies has a detrimental effect on health behaviour of migrant groups.
Physical inactivity is common in migrants and this appears to be a key factor
contributing to chronic disease in this group.17
Case control and cohort studies have reported an inverse relationship between
physical activity and risk of colorectal cancer.5;18-23 When those in the highest and
lowest categories of physical activity are compared , a reduction in risk of colorectal
cancer of up to 60% has been reported.5 After adjustment for potential confounding
factors of age, obesity or diet, the association remains strong. Although the
association between exercise and colorectal cancer risk holds for colorectal cancer as
a whole, the association is not seen when rectal cancer alone is considered.5
Consistent with the observation above is the finding that exercise may influence the
development of adenomatous polyps. The incidence rate ratio for the finding of
colonic adenomas amongst African-American women was 0.94 and 0.72 for groups
with low physical activity ( <5 metabolic equivalent (MET)-hours/wk) and high
physical activity (≥40 MET-hours/wk), respectively (Ptrend = 0.01).24
A number of potential mechanisms whereby physical activity could reduce the risk of
colorectal cancer have been described. Increase in gastrointestinal transit time (with
increased exposure of colorectal mucosa to faecal carcinogens), altered immune
function, increased prostaglandin levels and alterations in gastrointestinal and
pancreatic hormone profiles have all been proposed to play a role.25
However, a stronger case could be made for the role of insulin and insulin-like
growth factor-I (IGF-I) in the development of colorectal cancer in people taking little
exercise.5 High levels of insulin and IGF-I are associated with low exercise levels.
High levels of IGF-I increase the risk of colorectal cancer. Conversely, elevated levels
of insulin-like growth factor binding protein (IGFBP)-3, which are associated with
reduced levels of IGF-I, are associated with a lower risk of colorectal cancer.26 This
explored in more detail below.
It is interesting to note that genetic mutations associated with development of
colorectal cancer have been linked to levels of physical activity. Mutations in both kras and p53 have been associated with reduced levels of physical activity. 27;28
Colonic adenomas that develop in patients with low levels of physical activity are
also more likely to harbor mutations in k-ras compared with individuals with higher
levels of physical activity.
Obesity
Increased consumption of energy-dense, nutrient-poor foods with high levels of
sugar and saturated fats, combined with reduced physical activity, have led to
obesity rates that have risen three-fold or more since 1980 in some areas of North
America, the United Kingdom, Eastern Europe, the Middle East, the Pacific Islands,
Australasia and China. The obesity epidemic is not restricted to industrialized
societies; this increase is often faster in developing countries than in the developed
world.29 The proportion of people classified as overweight or obese is high. In the
UK, 56% of women and 65% of men are overweight or obese,30 with higher rates
reported in the United States where 62% of women and 71 % of men are overweight
or obese.31 These figures are likely to increase further as the rate of childhood
obesity is increasing.32 In parts of Africa, the prevalence of obesity is as low as 5%.29
An elevated Body Mass Index (BMI) has been associated with both the development
of colonic adenomas and colorectal cancer,18 33-36 with raised bodyweight thought to
account for up to 11% of colorectal cancer.37 It has been estimated that the relative
risk of developing colorectal cancer in obese men and women is 1.24 – 1.59 and
1.09 – 1.22, respectively.38 The association is stronger for distal colonic lesions
compared with proximal lesions. Visceral adiposity is a stronger risk factor for
development of colorectal cancer compare than BMI alone with reports of an
elevated risk of colorectal cancer in patients with higher waist-to-hip ratios. 39-41
Obesity is associated with the metabolic syndrome which encompasses a group of
clinical measures including abdominal obesity, impaired glucose tolerance,
hyperinsulinaemia, hyperlipidaemia and hypertension. The driving force for the
development of metabolic syndrome is either the presence insulin resistance or
visceral adiposity.38 Clusters of some of the factors that make up the metabolic
syndrome have been associated in population cohort studies with an increased risk
of colorectal cancer.42-44
In vitro studies have demonstrated that insulin promotes cellular proliferation and
inhibits cellular apoptosis in colon cancer cell lines 45;46 and promotes the growth of
colorectal cancer in animal models. The effect of the hyperinsulinaemia may be
mediated by the IGF system. 38 Hyperinsulinaemia is associated with elevated levels
of IGF-I which has itself been associated with an increased risk of colorectal cancer.47
In in vitro studies, IGF-1 has been demonstrated to promote cell migration, cell
proliferation and angiogenesis and inhibit apoptosis and cellular adhesion via
mechanisms that include increased production of hypoxia inducible factor (HIF) 1,
vascular endothelial growth factor (VEGF) and activation of Wnt-signaling.38
Obesity is associated with increased serum levels of leptin and inversely associated
with adiponectin levels. Alterations in levels of these adipocytokines have effects on
cell proliferation, angiogenesis and promotion of tumourigenesis in in vitro studies
that could contribute to the development of colorectal neoplasia in obese
individuals.48;49
Visceral adiposity has also been associated with a state of chronic, low-grade
inflammation with persistent activation of the nuclear transcription factor NKkappaB
with subsequent transcription of genes that promote tumourigenesis.38
It is unclear whether interventions to reduce weight could have an impact on the
development of colorectal cancer. Sustained weight loss among obese patients is
rare,50 and adequately powered studies to investigate this have not been performed.
Diet
The diet in Western countries is characterised by increased quantities of processed
foods, red meat and reduced dietary fibre compares to those diets in developing
countries. A protective effect against colorectal cancer could be exerted by fibre,
antioxidant vitamins, folic acid, flavones and other micronutrients.51
Some observational studies have reported that diets that are low in fruits and
vegetables are associated with an increased risk of colorectal cancer. 52;53 When
groups with the highest and lowest intake of vegetables are compared, the relative
risk of colorectal cancer is approximately 0.5.51;53 In a large prospective investigation
into the impact of fruit and vegetable consumption on development of colorectal
cancer, a difference in fruit and vegetable consumption of one additional serving per
day was associated with a covariate-adjusted RR of 1.02 (95% confidence interval
[CI] = 0.98-1.05).54
A higher intake of fibre has been associated with a reduced risk of colorectal cancer
in some studies, 55-58 but not in others.54;59 A large prospective study of 88 757
women, failed to demonstrate a protective effect of dietary fibre on the risk of
colorectal cancer, with a relative risk of 0.95 (95% CI, 0.73 - 1.25) for the highest as
compared with the lowest quintile group with respect to fibre intake.59 A Cochrane
systematic review of randomised controlled trials that included five studies and a
total of 4349 subjects concluded that there was insufficient evidence to conclude
that increased dietary fibre intake reduces the incidence or recurrence of
adenomatous polyps within a two to four year period.60 In a pooled analysis of 13
prospective cohort studies dietary fiber intake was inversely associated with risk of
colorectal cancer in age-adjusted analyses (RR =0.84; 95% CI, 0.77 - 0.92).61
However, after adjusting for other risk factors, the relative risk was no longer
statistically significant.
The significance of fruit, vegetables and fibre is therefore unclear, with studies
reporting contradictory results. It is not yet possible to draw firm conclusions as to
the potential role of these dietary factors.
Proposed mechanisms by which dietary fibre could reduce the development of
colorectal cancer have included decreased exposure of the colonic mucosa to
carcinogens and the fermentation of fibre by the colonic microbiota to produce the
short chain fatty acids acetate, propionate and butyrate.62 Butyrate has been
demonstrated to induce cell-cycle arrest, differentiation and/or apoptosis in vitro,
but in vivo studies of the effect of butyrate have provided conflicting results.63
Although there is some inconsistency in reports, observational studies have reported
an association between red meat consumption and the development of colorectal
cancer, with no increased risk reported for poultry and fish intake. 5 A prospective
study examining the outcome of consumption of red meat, poultry, fish and
processed meat on development of colorectal cancer red meat reported a Relative
Risk (RR) of 1.71 (95% CI, 1.15-2.52; P=.007) for development of rectal cancer. In the
same study, processed meat was associated with an increased risk of distal colon
cancer (RR = 1.50; 95% CI, 1.04-2.17).64 A meta-analysis of observational studies has
examined the association of ingestion of red meat and processed meat with
development of colorectal cancer. The relative risk for individuals in the highest
quartile of consumption for red meat was 1.35 (95% CI, 1.21-1.51) and for those in
the highest quartile for consumption of processed meat, the relative risk was 1.31
(95% CI, 1.13-1.51).65
The haem content of red meat could promote the development of colorectal cancer.
66;67
Red meat and haem iron supplement ingestion increase faecal levels of N-
nitroso compounds 68;69 Processed meat has also been found to contain N-nitroso
compounds. 70;71 This observation may be significant, as N-nitroso compounds are
potentially carcinogenic. Some classes of N-nitroso compounds have alkylating agent
properties and have been demonstrated to induce GC to AT transitions at the second
base of codon 12 or 13 in k-ras gene.72
Red meats and haem supplementation have also been associated with increased
levels of DNA adducts within colonocytes. DNA adducts are highly reactive agents
that react with nucleophilic centres in DNA bases and have been recognised as
playing a central role in carcinogenesis.73
The cholesterol content of the diet may also influence colorectal cancer risk. In an
observational study examining the relationship between habitual food consumption
and risk of colorectal cancer, the relative risk between the highest and lowest
quartiles of dietary cholesterol was 3.26 (95% confidence interval 1.54-6.88). 74
Smoking and alcohol
The World Health Report in 2002 highlighted the problem of increasing alcohol use
and smoking in recent decades, particularly in developing countries which still,
however, have lower rates of alcohol consumption and smoking-related disease than
developed countries.16
An increased relative risk of colorectal neoplasia among smokers has been reported
in a number of observational studies. 5 In a case-control study, the odds ratio for
development of adenomatous polyps in patients who smoke was 1.8 75 Prospective
studies have reported a relative risk of colon cancer of between 1.2 and 1.4 and a
relative risk of 1.4 to 2.0 for rectal cancer. 5 These associations should be interpreted
with caution as there is currently insufficient data to establish a causal relationship
between smoking and colorectal neoplasia.
It has been suggested that smoking may be associated only with particular tumour
sub-types. In a population-based case-control study on sporadic colorectal cancer,
cigarette smoking status was significantly differently related to p53 overexpressionpositive tumours (p53pos) compared to p53 overexpression-negative tumours(p53neg)
(p53pos versus p53neg, OR 0.4, 95% CI 0.2 - 0.9).76 Similarly, cigarette smoking status
was significantly differently related to tumours with transversion mutations in APC,
K-ras or p53 (transv+) compared with tumours without transversion mutations in one
of these genes (transv-) (transv+ versus transv-, OR 2.5, 95% CI 1.0 – 5.9).76 There was
no clear association between smoking status and MSI in this study, but it has been
reported elsewhere that smoking may be associated with a mismatch repair (MMR)
mutations which are associated with MSI.77;78
Alcohol
As with other environmental factors associated with colorectal cancer, there is some
disagreement as to the potential contribution that heavy alcohol use may make to
the development of colorectal cancer. In a pooled analysis of data from eight cohort
studies, the relative risk of developing colorectal cancer in those drinking > 45 g/d
was 1.41 (95% CI, 1.16 - 1.72). 79 Lower levels of alcohol intake were not associated
with an increased risk. (Relative risk 1.16 (95% CI, 0.99 to 1.36) for patients who
admitted to drinking 30 - 45 g/d). It has been suggested that a decrease in intake of
folate in patients with significant alcohol dependency could explain the observation
of a higher risk of colorectal cancer in this group.80;81
Conclusions
There is marked worldwide geographical variation in the incidence of colorectal
cancer with higher levels reported in developed countries. Modifiable lifestyle
factors are thought to contribute substantially to this marked variation. Results of
studies investigating the association between fibre, fruit and vegetables and
colorectal cancer are contradictory and firm conclusions cannot be drawn. Red meat
and processed meat consumption is associated with an increased colorectal cancer
risk. Smoking, alcohol and obesity are also associated with colorectal cancer.
Mechanisms whereby these lifestyle factors may influence molecular pathways
implicated in colorectal carcinogenesis have been described.
In some developed countries, rates of colorectal cancer have stabilized or even
reduced. Although economic development has been associated with lifestyle
changes associated with an increased risk of colorectal cancer, it may also provide a
means to modify that risk. Development of screening programmes, initiatives to
tackle inequalities in access to education and improved access to health care may all
play a part in reducing the risk of colorectal cancer in these countries.82
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