An overview of apoptosis and the prevention of colorectal cancer

Critical Reviews in Oncology/Hematology 57 (2006) 107–121

An overview of apoptosis and the prevention of colorectal cancer Alastair J.M. Watson ∗ Division of Gastroenterology, School of Clinical Science, University of Liverpool, Liverpool, UK Accepted 29 June 2005

Contents 1. 2.

3.

4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular pathogenesis of colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Chromosomal instability and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Adenomatous polyposis coli (APC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. SURVIVIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. c-Myc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Ras . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. TGF-␤ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. p53 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.7. DCC and Netrin 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.8. Inflammation and colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.9. Microsatellite instability and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apoptosis and prevention of colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Diet. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Vegetable products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

108 108 109 109 110 110 110 111 111 112 112 113 114 114 114 114 114 116 116 116 121

Abstract Colorectal cancer arises as a result of the accumulation of genetic errors many of which affect the control of apoptosis. Effective chemoprevention strategies for colorectal cancer must rectify these genetic defects. Mutation of apc is often the initiating genetic lesion in colorectal cancers that develop along the chromosomal instability pathway. Depending on the cellular context, loss of apc activates the Wnt signalling pathway causing immediate widespread apoptosis of colorectal epithelial cells and defects in differentiation and cell migration. Only cells that are inherently resistant to apoptosis survive this initial wave of apoptosis. These surviving cells constitute the epithelial population that develop into adenomas. Two gene targets of the Wnt signalling pathway are of particular relevance to apoptosis. Although controversial, survivin may function to inhibit apoptosis. MYC has two outputs in normal cells, the induction of apoptosis and proliferation. These opposing functions work so that MYC can only induce cell proliferation in cells if apoptosis is disabled. p53 couples apoptosis to mitogenic signals and survival pathways. Under some circumstances, NF-␬B can act as an inhibitor of apoptosis possibly through increased expression of bcl-xL . Tumours that evolve by the microsatellite instability pathway often have mutations in the proapoptotic gene bax. Colonic adenomas express cyclo-oxygenase-2 (COX-2) and may be targets of chemoprevention before the development of malignancy. However, the recent discovery ∗ Present address: Department of Medicine, University of Liverpool Medical School, Daulby Street, Liverpool L69 3GA, UK. Tel.: +44 151 706 4074; fax: +44 151 706 5802. E-mail address: [email protected].

1040-8428/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2005.06.005

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that coxibs increase the risk of serious cardiovascular events limits their use as chemopreventive agents. Nevertheless, aspirin remains a drug of great interest as it is already known to reduce the risk of colorectal cancer by up to 50%. The balance of evidence shows that high vegetable fibre diets can prevent colorectal cancer, probably via the fermentation of butyrate enhancing the apoptotic response to DNA damage. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Animals; Apoptosis; Drug resistance; Colorectal cancer; Humans; Neoplasms/genetics/*pathology; Oncogene proteins/genetics/*metabolism; Protein p53/metabolism; ras; survivin; tgf-β; COX; myc; apc; NSAIDs; Vitamin D; Curcumin; Butyrate

1. Introduction

2. Molecular pathogenesis of colorectal cancer

On a global scale, colorectal cancer is the fourth commonest malignant neoplasm after lung, breast and prostate [1]. As will be discussed below, approximately 90% of colorectal cancers are derived from benign adenomatous lesions which are estimated to take 5–15 years to evolve into invasive cancer (for review, see [2,3]). A wealth of epidemiological and clinical trial data suggests that if these premalignant lesions are identified and removed, the subsequent development of colorectal cancer is aborted [4–6]. Unfortunately, adenomas are largely asymptomatic and so require population-based screening programmes for their detection. Colorectal cancer develops through a number of well characterized stages based on the degree of invasion. When the cancer is confined to the wall of the bowel (Stage 1, T1 N0 M0 ), resection is essentially curative with 5 year survival rates of 90% or more. However, in Stage IV disease where distant metastases are present, the 5 year survival drops to 15% [7]. Overall, the 5 year survival rate of colorectal cancer is 50%. These diagnostic challenges have led investigators to attempt to prevent adenoma formation with the minimum of risk. The long natural history of adenomas, their accessibility to biopsy and the existence of two inherited forms of colorectal cancer whose genetic changes mirror those of sporadic cancer have enabled investigation of molecular pathogenesis of sporadic colorectal cancer in great detail, perhaps more than any other neoplasm [8]. These investigations have shown that numerous errors in pathways controlling apoptosis (programmed cell death) occur during the development of colorectal cancer. These abnormalities render cells with clinically significant mutations resistant to elimination through apoptosis (programmed cell death). Abnormalities in core apoptosis mechanisms go hand in hand with inherent resistance to chemotherapy and radiotherapy. Clinical evidence is emerging that defective apoptosis is of pathogenic significance [9]. Apoptosis rates in rectal mucosa are inversely related to the presence of adenomas, while the clinical response of adenomas to treatment with the COX-2 inhibitor celecoxib correlates positively with apoptosis [10,11]. Thus, a full understanding of molecular abnormalities in apoptosis and its relationship to other molecular pathogenic mechanisms is essential for the rational development of prevention strategies against colorectal cancer.

Hahn and Weinberg have argued that a normal cell has only to acquire six phenotypes in order to behave as a fully transformed malignant cell. These phenotypes are resistance to growth inhibition, immortalization, independence from mitogenic stimulation, the ability to acquire their own blood supply, the ability to invade and metastasize and the ability to suppress or evade apoptosis [12]. These characteristics are acquired through the mutation of key genes regulating these functions. The deletion of stem cells harbouring malignant mutations by apoptosis is of particular interest as a vital defence mechanism against the formation of colorectal cancer. Most investigators agree that normal cells do not mutate sufficiently frequently to attain all the genetic errors required to generate a full set of malignant phenotypes in a human lifetime. For this to occur, the genome of a cell must become unstable in order to accumulate genetic errors at a rate sufficiently fast for cancer to develop. In the case of colorectal cancer, genetic instability develops in two ways, 85% of tumours display chromosomal instability in which chromosome translocations or alterations in number occur. The remaining 15% have microsatellelite instability where basepair mismatches are not recognised or repaired causing frameshift mutations in microsatellite repeats throughout the genome. Such genetic errors would normally trigger death of the cell through the induction of apoptosis. However, in colorectal cancer, the signalling and effector pathways of apoptosis are progressively inactivated thereby permitting the accumulation of genetic errors (Fig. 1).

Fig. 1. The intrinsic, or mitochondrial, pathway to apoptosis.

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There are a number of biological and clinical differences between colorectal cancer from the left and right colon [13]. While there is little doubt that left sided colorectal cancers develop from adenomas, it has been suggested that right sided cancers may develop de novo from depressed type lesions [14]. Also, there are significant differences in gene expression between right and left sided lesions [15]. Right sided cancers also have a better prognosis than left sided tumours and are commoner in women, whereas left sided tumours are commoner in men [16,17]. 2.1. Chromosomal instability and apoptosis Colorectal adenocarcinomas develop through a well defined series of histological stages from normality to dysplastic small adenomous polyps to highly dysplastic large polyps to cancer. A minority of cancers develop from flat or depressed polyps. Some investigators suggest they are more frequently highly dysplastic than polyploid adenomas though this has recently been disputed [18]. Chromosomal instability develops very early in the natural history of the development of polyps and usually consists of chromosomal additions or deletions (Fig. 2). Later in the progression of colorectal cancer aneuploidy develops. As many as 11,000 genetic errors occur in adenomas and these accumulate progressively during the transition of adenomas into frank cancer [19,20]. 2.1.1. Adenomatous polyposis coli (APC) apc encodes a cytosolic protein of 2843 amino acids. Mutation of apc occurs very early in the development of adenomas and causes inappropriate activation of the Wnt signalling pathway and chromosomal instability [8,21]. APC can act in concert with a protein called EB1 to stabilise spindle microtubules during mitosis [22–24]. Mutation of apc results in errors in the connections between microtubules and kinetochores resulting in abnormal chromosomal segregation. Studies of mouse embryonic stem cells have found

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that apc mutations cause polyploidy. The significance of apc mutation as a cause of chromosomal instability in early development of colonic adenomas is uncertain as chromosomal additions and deletions are far more characteristic of early adenomas and are not caused by mutation of apc [25,26]. Perhaps more importantly, APC plays a critical role in regulating gene transcription through the Wnt signalling pathway. The function of this pathway is to control the activation of gene transcription by ␤-catenin. In the absence of Wnt signalling ligands, ␤-catenin is held in the cytosol in a protein complex with APC, axin and glycogen synthase-3␤ (GSK-3␤). ␤-Catenin levels are kept low through phosphorylation by serine/threonine kinases, casein kinase and GSK-3␤ which targets it to ubiquitination and degradation. Wnt ligands are lipid-modified signalling proteins that normally regulate mammalian development. To date, 19 have been identified and have been implicated in the growth of the renal and gastrointestinal tracts [27,28]. These ligands bind to a receptor called frizzled (named after the appearance of Drosophila fruit flies lacking this receptor). Wnt signalling activates an intermediate protein called Dishevelled (Dsh) which inhibits GSK-3␤ thus preventing degradation and causing accumulation of ␤-catenin in the cytosol from where it translocates to the nucleus. Here, it binds to the transcription cofactor T-cell factor/lymphoid enhancement factor (TCF/LEF) activating a gene programme in which there are changes in the expression of over 500 genes [21]. Mutant APC cannot hold ␤-catenin in a complex with axin and GSK-3␤. This prevents the targeting of ␤-catenin for degradation and causes persistent activation of the Wnt pathway. Until recently, the primary physiological consequences of apc mutation were unknown since its ablation in conventional knockout mouse models caused death of the embryo. Sansom et al. recently developed a new model in which a lox-flanked apc allele was crossed into an inducible cre background in which cre expression is controlled by

Fig. 2. The chromosomal instability pathway to colorectal cancer.

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the Cyp1A promoter [21,29]. Activation of the promoter by injecting the mice with ␤-naphthoflavone causes ablation of apc in intestinal epithelial cells. The effect of knockout of apc on the structure of the intestinal epithelium in the adult mouse is spectacular. Migration of epithelial cells along the crypt/villus axis is disturbed, positional cues are lost and differentiation stops. The cells become polyploid, mitosis increases and are no longer confined to the base of the crypt. Apoptosis also increases dramatically in the first few days after deletion of APC through mechanisms that are not fully understood. This cell loss puts a strong selection pressure in favour of cells that have an apoptosis-resistance phenotype. 2.1.2. SURVIVIN One of the genes that is upregulated by the T-cell factor/␤catenin pathway following mutation of APC is the bifunctional regulator of apoptosis and cell proliferation survivin [30–32]. Survivin is a member of the inhibitor of apoptosis (IAP) family which is defined by their ability to inhibit apoptosis and the presence of at least one Baculovirus IAP Repeat (BIR) domain [33]. Survivin is the shortest member of the family and has only one BIR domain [34]. Some members of the IAP family bind and inhibit CASPASES. For example, XIAP can bind CASPASE 9 through its BIR 3 domain and also binds to CASPASE 3 and 9 through the linker region between BIR1 and BIR2. However, the mechanism by which SURVIVIN inhibits apoptosis is not fully understood currently. Some studies have shown that SURVIVIN can bind CASPASE 3 and 7 [35] but this has been questioned by studies showing that SURVIVIN does not have the correct structure for high affinity binding to CASPASES [36]. There is evidence that SURVIVIN may inhibit CASPASE 9 indirectly by binding to Hepatitis B X-protein which in turn binds CASPASE 9 [37]. Another possibility is that SURVIVIN binds to SMAC/DIABLO, one of the proapoptotic proteins released by mitochondria during apoptosis, preventing it from binding to other IAPs thereby allowing caspase activity that is uninhibited by IAP binding [38,39]. Such a mechanism may account for how survivin inhibits apoptosis induced by taxol [40]. However, this mechanism is not universal as survivin does not prevent the induction of apoptosis in ovarian cancer cells by SMAC [41]. Survivin has been shown to enhance Fas ligand expression in colorectal cancer cells thereby augmenting the extrinsic pathway of apoptosis [42]. SURVIVIN also plays an important role at the G2 /M checkpoint of the cell cycle at which time it is specifically expressed [43]. During mitosis, it binds to microtubules through Aurora B kinase and disruption of this binding causes cell division defects [44,45]. One way in which this bewildering array of mechanisms can be reconciled may be through an appreciation of the subcellular localisation of SURVIVIN. When in the cytoplasm it acts to suppress apoptosis but when in the nucleus it acts as a chromosomal passenger protein at the G2 /M checkpoint [46].

2.1.3. c-Myc Deregulation of the myc family of transcription factors and its consequences is one of the most intensively studied areas in cancer biology [47]. Their target genes are mostly involved in cell metabolism, ribosome biogenesis and translational control [48]. Myc itself is a target of TCF/␤-catenin signalling and so is overexpressed in 70% of colorectal cancers [49]. Its degradation has one of two functional outputs: increased apoptosis and increased cell division [50]. The potent proliferative response to myc in untransformed cells is not unleashed unless apoptosis is disabled. However, if apoptosis mechanisms are intact, MYC expression increases cellular sensitivity to DNA damage-induced apoptosis [51]. MYC expression is also important in determining the action of p53 in response to DNA damage. In the presence of low levels of MYC, p53 causes the upregulation of the cyclindependent cyclin inhibitor p21Waf1/Cip1 causing cell cycle arrest and DNA repair [52]. A high level of MYC interacts with MIZ-1 to downregulate p21Waf1/Cip1 thus favouring the apoptosis response to p53 [53]. Recent data suggest an additional mechanism by which myc might promote cancer growth. Studies of wing growth in Drosophila have shown that cells with high levels of MYC outgrow and induce apoptosis in neighbouring cells with lower levels of MYC [54,55]. In situations with limited quantities of cell survival factors, cells with high MYC levels could outgrow and kill neighbouring cells with low MYC. The death of neighbouring normal cells may be of particular importance in allowing expansion of a clone of neoplastic cells. For example, it is known that normal cells can suppress the growth of cells transformed with ras. Such inter-cell competition may explain the well-known phenomenon of “field cancerisation” where a clone of genetically altered neoplastic cells grow and replace normal cells [56]. This accounts for dysplastic field lesions often seen on colorectal neoplasia. A logical, but counterintuitive, corollary of these ideas is that inhibition of apoptosis in normal cells may prevent competition from a neoplastic MYC overexpressing cells restraining tumour growth [56,57]. Such ideas show just how difficult it can be to predict the functional and structural outcomes of apoptosis in the complex environment of the living mammal. 2.1.4. Ras The three RAS proteins (H-RAS, K-RAS and N-RAS) are GDP/GTP controlled switches which are activated by binding GTP. A number of receptors including G protein coupled receptors and tyrosine kinase coupled receptors activate RAS. A set of three kinase pathways (RAF, MEF and MAPK) mediate the biological effects of RAS by activating gene transcription [58–60]. Activating mutations of ras occur in approximately 40% of colorectal adenoma and carcinomas suggesting the RAS–RAF–MAPK pathways are important at the adenoma/carcinoma transition [61–63]. However, the mechanism through which ras mediates progression of colorectal cancer is unclear. Activation of ras in mouse models does not cause colorectal cancer. Moreover, little is known

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about the role of the RAS–RAF–MAPK pathway in the regulation of cell number on the crypt/villus axis. Nevertheless, suppression of RAS by kinase suppressor of RAS-1 (KSR1) has an antiapoptotic effect [64]. Disruption of KSR1 increases apoptosis in TNF-treated intestinal epithelial cells [65] which may have an influence on cancer formation [66]. 2.1.5. TGF-β Transforming Growth Factor-␤ (TGF-␤) is a member of a superfamily of growth factors that regulate cellular proliferation, differentiation, migration, embryonic development, wound healing and angiogenesis [67]. The TGF-␤ family of cytokines binds and dimerises the types I and II TGF␤ receptors. These are serine-threonine kinases and their heterodimerisation results in the phosphorylation of type I receptor by the type II receptor. Intracellular signal transduction of TGF-␤ signalling is undertaken by the SMAD proteins. Receptor-regulated SMADs (R-SMADs: SMAD −1, −2, −3, −5 and −8) are anchored to the cell membrane by interaction with membrane bound proteins. Commonpartner SMAD (SMAD-4) forms complexes with receptor SMADs when the latter are phosphorylated by the TFG-␤ receptors. The oligomeric SMAD complexes then translocate into the nucleus, where they regulate the transcription of target genes. A third class of SMADs, inhibitory SMADs (I-SMADs: SMAD −6 and −7), inhibits the signals from the serine/threonine kinase receptors. Since the expression of ISMADs is induced by the TGF-␤ superfamily proteins, they act as a feedback loop [68]. Inactivating mutations of the TGF-␤ signalling pathway frequently occur during the progression of an adenoma to a carcinoma. Mutations in TGF-␤ receptor type II occur in most microsatellite unstable tumours and in 55% of microsatellite stable tumours [69,70]. In normal intestinal epithelium, TGF␤ receptors are expressed in differentiated surface epithelial

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cells. Their activation causes growth inhibition in the G1 phase of the cell cycle. This cytostatic effect is lost in neoplastic transformation. Mice with inactivation of TGF␤R type II have an increased susceptibility to the establishment and progression of colorectal cancers induced by azoxymethane [71]. Apoptosis does not appear to play a role in this model. However, SMAD 3 overexpression causes apoptosis in prostate, lung and liver epithelial cells [72–74]. Recent results from study of SMAD3 deficient colonic epithelial cells show them to be markedly resistant to the induction of apoptosis by TGF-␤. The mechanisms of resistance to apoptosis are not fully understood but do not appear to involve BCL-2 family members [75]. Furthermore, SMAD3 deficient mice develop colorectal cancer [76]. 2.1.6. p53 P53 is a transcription factor placed at the nexus of a number of pathways that mediate apoptosis in response to a wide range of cellular stresses. These include DNA damage, hypoxia and nutrient deprivation, cell survival and proliferation [77,78]. P53 couples stimuli that promote cell division to those that promote cell death. For this reason, P53 is one the most critical molecules in determining oncogenic transformation and the response of cancer to chemotherapy and radiotherapy. A number of oncogenes can also induce p53 including myc, the adenovirus early region 1A (E1A) and the transcription factor E2 F. In doing so, p53 protects the organism against neoplastic transformation by acting as a sensor for excessive proliferation signals eliminating such abnormal cells by apoptosis [78] (Fig. 3). A number of experimental models have demonstrated that inactivation of p53 or downstream apoptosis genes can result in transformation and tumourigenesis, illustrating the importance of apoptosis as one of the protective mechanisms against cancer development. The

Fig. 3. Mitogenic signals are transduced by Ras which inhibits the retinoblastoma (Rb) protein allowing E2F and Myc to promote cell cycle progression. p16INK4a is a tumour suppressor whose mutation permits cyclin D dependent kinase (CDK) to inhibit Rb. High levels of E2F or Myc activates p14ARF and thereby p53 which has multiple outputs. A series of proapoptotic bcl-2 family members are stimulated and via PTEN the antiapoptotic actions of AKT are inhibited. Note that p53 can still respond to DNA damage, and therefore chemotherapy, if the Ras/Rb pathway is disabled.

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induction of p53 by MYC, E2 F and E1A is mediated by p14ARF [79,80] and elimination of p14ARF increases the promotion of carcinogenesis by Myc by eliminating the apoptotic response [81]. By contrast, induction of p53 by DNA damage is not mediated by p14ARF . Thus, tumours in which p53 is inactive because of p14ARF mutation will still be sensitive to DNA damaging drugs [78]. Target genes regulated by p53 include the proapoptotic bcl-2 family genes puma, noxa, bid and bax, the death receptor genes, Fas/CD95 and DR5, and the mitochondrial pathway genes APAF-1 and caspase 6 [82–86]. In addition to promoting apoptosis, p53 also prevents the induction of the survival pathways. This is achieved by blocking the activation of AKT by PI-3 kinase via PTEN [87]. AKT coordinates survival by inhibiting the apoptosis proteins CASPASE 9, BAD, BAX and FAS/CD95 ligand. AKT also promotes the NF-␬B survival programme (see below) by stimulating I␬B kinase-␣ (IKK␣) [88]. The coupling of mitogenic signals from oncogenes to apoptosis and antisurvival pathways by p53 is important for chemoprevention of cancer. One of the goals of chemoprevention is to eliminate neoplastic clones of cells before invasion without damaging normal cells. Mutations that remove the link between proliferation and apoptosis, for example in p53, will enable proliferation to take place without simultaneous apoptosis thereby increasing their drug resistance. On the other hand, the coupling of mitogenesis to apoptosis has the counterintuitive effect that cells driven to divide by oncogenes are more sensitive to apoptosis-inducing agents than normal cells [78]. Thus, preneoplastic lesions are obliged to evolve mechanisms to prevent this tendency to undergo apoptosis. In contrast, normal cells do not require proapoptotic oncogenic mutations. As proliferation is not being driven forward by oncogenes, the coupled apoptotic pathways will be quiescent leaving such cells a high threshold for apoptosis protected in stress-free growth factor rich niches. Thus, reactivation of p53-induced apoptosis or inhibition of PI-3 kinase-induced survival responses is effective anticancer strategy in a number of animal models [89,90]. 2.1.7. DCC and Netrin 1 Deleted in colorectal cancer (DCC) is the mystery gene of colorectal cancer. It was identified as a tumour suppressor gene for colorectal cancer in classic studies by the Vogelstein group in the early 1990s. It is located at a locus on chromosome 18q that is deleted in 70% of colorectal cancers [91]. However, its status as a colorectal cancer gene has not been accepted as mice with mutant DCC do not develop colorectal cancer [92]. DCC is a member of the so called dependency receptor family along with RET, ␤-integrins, Patched and the p75 neurotrophin receptor all of which induce apoptosis when not bound by their respective ligands. In the case of DCC, the ligand is called NETRIN-1 which is a diffusible laminin related gene that has a well defined role in directing axon migration during the development of the nervous system [93]. A recent study has demonstrated that when netrin-1 is

overexpressed in epithelial cells of the mouse intestine apoptosis is suppressed and tumour growth is promoted. When NETRIN-1 is overexpressed in mice which are heterozygous for the apc gene, the growth of adenoma and their transformation into cancer is greatly enhanced [94]. Mazelin et al. suggest that DCC is a “conditional” tumour suppressor since it only acquires suppressive properties when ligand availability is limited or absent. As a corollary to this, it acts as a tumour promoter when ligand binding is abundant. 2.1.8. Inflammation and colorectal cancer For over a century, since pioneering observations by Virchow, it has been known that chronic inflammation is sometimes associated with cancer [95]. Tumours often exist in an inflammatory environment rich in pro-inflammatory cytokines such as TNF␣, IL-1, IL-6, IL-8, reactive oxygen species and prostaglandins that promote DNA damage, angiogenesis, inhibition of apoptosis and cell invasion. Inflammatory bowel disease predisposes to the development of colorectal cancer [96]. Some studies have found the incidence to be as much as 40% in patients who have suffered from IBD for 40 years. However, modern aggressive treatment of inflammation with 5-ASA compounds can virtually eliminate this excess risk [97]. 2.1.8.1. NF-κB. NF-␬B is one of the principal transcription factors regulating the inflammatory response [98]. Recent studies have implicated NF-␬B in the growth of colorectal cancer [99]. In the resting condition, NF-␬B is a protein complex composed of RelA and p50 and this is held in the cytoplasm by the inhibitor protein I␬B (Fig. 4). When triggered by infective microorganisms or proinflammatory cytokines such as TNF-␣, I␬B kinase (IKK) phosphorylates the I␬B protein attached to NF-␬B and targets it for degradation. The released NF-␬B translocates to the nucleus where it activates a programme of gene transcription. Disabling this pathway in colonocytes by knocking out IKK in the context of colonic inflammation dramatically reduces the growth of carcinogen-induced colorectal tumours. This may be because NF-␬B stimulated transcription causes expression of the antiapoptotic protein BCL-XL [99]. This does not occur in enterocytes lacking IKK which are consequently more prone to deletion by apoptosis after exposure to a carcinogen. The tissue location of NF-␬B is important in determining its effects. Deletion of IKK in macrophages reduces tumour initiation. It does not influence apoptosis but instead reduces expression of COX-2 whose products have tumour promoting properties. An intriguing area for future investigation is the relationship between gut microflora and NF-␬B activation and tumour suppression. The binding of organisms to toll-like receptors on enterocytes activates survival and anti-apoptosis mechanisms by pathways including NF-␬B [100]. Although epidemiological studies have clearly shown a causal relationship between food constituents and colorectal cancer risk, the mechanisms of this risk remain unclear [101]. One plausible hypothesis is that each food component promotes different

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Fig. 4. The classical NF-␬B pathway and its activation by bacteria. After reference [98].

species of gut microflora some of which promote carcinogenesis and others of which are protective. Identification of microflora that activate survival and anti-apoptosis pathways through toll-like receptors and NF-␬B might reveal important mechanistic relationships between food and cancer risk (Fig. 5). Such investigations might reveal the relationship between food components that promote particular populations of microflora and colorectal cancer risk. 2.1.9. Microsatellite instability and apoptosis Microstatellite instability (MSI) is the result of inactivation of a system of proteins that repair basepair mismatches during DNA replication. This type of genetic instability can be identified through detection of frameshift mutations throughout microsatellite repeats all over the genome. Clinically, this is defined as at least two unstable loci out of five of a panel of standard loci [102]. This abnormal repair of DNA accounts for the familial syndrome Hereditary Non-

Polyposis Colorectal Cancer (HNPCC) and also about 15% of sporadic colorectal cancers. Loss of mismatch repair capability can occur either through mutation of mismatch repair genes themselves or by the silencing of mismatch repair genes without mutation. Aberrant methylation of CpG islands in the promoter of MLH1 can silence its expression and cause MSI [103]. MSI colorectal cancers accumulate mutations at rate up to 1000 greater than normal cells [104]. Genes that possess microsatellite repeats are particularly prone to such mutations. This gives MSI colorectal cancers a characteristic repertoire of frequent mutations such as bax, tgf-β type II, activin type II receptor, msh3 and msh 6 [105,106]. Conversely, mutation in p53 is less frequent than in microsatellite stable colorectal cancers. This may be because mutations of the proapoptotic gene bax are also common in MSI tumours and may be able to replace the function of p53 mutation by creating a state of relative apoptosis resistance [26]. Furthermore, mutation of mismatch repair genes themselves may

Fig. 5. A speculative model for initiation of colorectal cancer by gut flora.

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lead to apoptosis resistance. Studies in msh2 deficient mice have shown intestinal epithelial cells to be resistant to apoptosis induced by methylating agents such as temozolomide [107]. Genome wide DNA damage can signal apoptosis via hMSH2, hMSH6 and hMLH1 by pathways mediated by cABL, P73 and P53 [107–109].

[124], n-3 fatty acids [125,126] and glucosinolates from brassica vegetables [127]. Curcumin, a dietary compound from turmeric, is known to induce apoptosis in a variety of colorectal cancer cells by mechanisms involving the proapoptotic protein BAX and activation of c-JUN N-terminal kinase [128,129]. 3.2. Vitamin D

3. Apoptosis and prevention of colorectal cancer 3.1. Diet 3.1.1. Vegetable products A number of dietary components have been reported to cause apoptosis with the implication that mutant cells will, in this way, be eliminated thereby preventing cancer. Such inferences are fraught with difficulty as modulation of cell death may not necessarily be responsible for cancer protection in the complex environment of the human gut [110]. Diets high in fibre (non-starch polysaccharides) have been recommended to prevent colorectal cancer [111,112]. Epidemiological studies and intervention studies have not consistently demonstrated a protective effect. However, a recent very large prospective study of dietary intake and cancer (EPIC) designed to overcome some of the shortcomings of earlier studies has demonstrated that a high fibre diet confers a reduction in relative risk of up 0.6. Of interest, the protective effect was the same in right and left colon. The source of the fibre did not influence the protective effect. The short chain fatty acids, acetate, propionate and butyrate, are the major products of carbohydrate fermentation in the large bowel. Butyrate has attracted attention because in addition to being a fuel for energy production, it can induce apoptosis in colorectal cancer cells if the cells have a sufficient energy supply from other substrates [113]. Butyrate is probably the first chemopreventive agent to be reported to act by induction of apoptosis. The induction of apoptosis by butyrate does not require functional p53 [114]. Its mechanism of induction of apoptosis is not fully understood, but it is known that butyrate opens up the chromatin structure of DNA, possibly enhancing the transcription of propaptotic genes [115]. Ras has also been reported to enhance butyrate-induced apoptosis via inhibition of the actin-binding protein gelsolin [116]. However, the importance of butyrateinduced apoptosis in preventing colorectal cancer in vivo is unclear. There have been reports of butyrate both increasing and decreasing carcinogen-induced apoptosis in rodent models with sometimes, but not always, a correlation with apoptosis [117–121]. The effect of fibre derived butyrate on human colonic carcinogenesis is unclear but one study has reported that supplementation of the diet with fibre increases adenoma formation [122]. The contribution of butyrate and apoptosis to this disturbing effect is not known [123]. Other food constituents have been reported to prevent colonic carcinogenesis in rodent models and human studies by increased apoptosis including fermented milk products

Vitamin D3 is a steroid hormone that regulates gene transcription by binding to a nuclear receptor, the Vitamin D receptor [130]. The most potent form of Vitamin D, 1␣,25dihydroxycholecaliferol, is synthesized from Cholecaciferol in the diet or from precursors in the skin. Common dietary sources are fatty fish such as mackerel, salmon or sardines or supplemented foods such as milk, orange juice or bread. Vitamin D-25-hydroxylase in the liver hydroxylates it to form 25-hydroxycholecalciferol which is further hydroxylated in the kidney by 25-hydroxyvitamin D3 -1␣hydroxylase to form 1␣,25-dihydroxycholecaliferol [131]. A number of case control and cohort studies have demonstrated an inverse relationship between calcium/Vitamin D and colorectal cancer end points [132–135], while other studies have found no association [132,136,137]. Supplementation of the diet with calcium causes a modest reduction in adenoma size and number [138–140]. Calcium supplementation only appears effective when the plasma concentration of 25(OH)D3 is above 75.6 nmol/L. Studies in rodents have provided further support for the protective effect of Vitamin D against colorectal neoplasia [141]. Vitamin D has a number of cellular effects that contribute to its anticancer effects in the colon including antiproliferation and differentiation [142–145]. Target genes include p21, p27/Kip1 causing cell cycle arrest and TGF-␤ causing growth inhibition. A number of groups have demonstrated that Vitamin D3 or analogues can cause apoptosis in the intestine [146–148]. High calcium Vitamin D intake is associated with increased apoptosis of colonic epithelium [149]. Its mechanism of induction of apoptosis is uncertain but has been associated with induction of the proapoptotic gene bak and a reduction in bcl-2 [148]. 3.3. NSAIDs There is a mass of epidemiological, laboratory and animal data that cyclo-oxygenase-2 (COX-2) promotes the growth of colorectal cancer and that induction of apoptosis is one of the mechanisms by which this protective effect is achieved. COX-2 is one of two cyclooxygenase enzymes that catalyse the conversion of arachidonic acid to Prostaglandin G2 [150–152]. The entire prostaglandin family of molecules is generated from this precursor. COX-1 is constitutively expressed and catalyses the production of prostaglandins in the gastric mucosa. A splice variant of COX-1 has been identified recently that is expressed in the brain and has been designated COX-3 by some workers [153]. COX-2 expres-

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sion is induced by inflammatory stimuli and catalyses the production of prostaglandins that mediate inflammation. In 1994, DuBois and co-workers discovered that it is expressed in 40% of colorectal adenomas and 85% of colorectal cancers and 100% of liver metastases [154–156]. These data are complimented by the observation that PGE2 levels are also elevated on colorectal cancers [157]. COX-2 expression is also elevated in intestinal adenomas of mice with a mutation of APC [158]. Together, these data support COX-2 as a potential chemotherapeutic target for the prevention of colorectal cancer. Mice with mutant APC that develop intestinal adenomas have a substantially reduced tumour burden if COX-1 or COX-2 is knocked out genetically or given COX-2 inhibitors [159–166]. In man, long-term consumption of aspirin or the COX-2 specific inhibitors rofecoxib and celecoxib can reduce the risk of developing colorectal cancer by as much as 50% [167–169]. Aspirin can also prevent recurrence of colorectal adenomas [170,171]. Treatment of patients with Familial Adenomatous Polyposis (FAP) with sulindac, celecoxib or rofecoxib can cause partial regression of adenomas [172–174]. Therapy of patients with liver metastases with rofecoxib for 26 days can decrease blood vessel density by 29% suggesting that metastatic growth would be reduced [169,175]. COX activity contributes to cancer development through at least six different mechanisms(for reviews, see [151,152,176]): inhibition of apoptosis [177–181], stimulation of angiogenesis [182–185], induction of invasiveness [186–189], modulation of inflammation [190,191] and immune-suppression and activation of carcinogens [192]. The importance of stimulation of apoptosis by NSAIDs is illustrated by the observation that apoptosis in human rectal biopsies is inversely related to the response of adenomas to

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NSAIDs [9]. Salicylates have been shown to induce apoptosis in vitro [193]. COX-2 activity increases Bcl-2 levels and activation of the AKT and MEK/ERK pathways both of which inhibit apoptosis [177,180,181,194]. NSAIDs have also been reported to inhibit the Wnt signalling pathway thereby reducing transcription of important downstream genes such as myc and survivin [195–197]. Another important target of the WNT pathway is the peroxisome proliferator-activated receptor delta and gamma (PPAR␦ and PPAR␥) [198–200]. This is a nuclear receptor that is activated by linoleic and arachidonic acid metabolites and directly activates a range of genes leading to acceleration of colorectal tumour growth [201–203]. Blockade of cyclooxygenase also causes the accumulation of arachidonic acid within the cell which can stimulate apoptosis [204]. A number of mechanisms by which NSAIDs induce apoptosis have been identified that occur independently of COX activity (Fig. 6). High concentrations of NSAIDs have been reported to induce apoptosis via BAX [205]. The NF-␬B pathway can be inhibited through direct action of NSAIDs against I␬B kinase [206]. An increase in sensitivity of cells to induction of apoptosis by death receptors has also been reported [207]. Epidemiological studies have shown increased risk of acute cardiac event in patients taking rofecoxib at doses above 25 mg/day [208,209]. Further evidence of possible cardiovascular risk came from the APPROVe study in which an increased rate of myocardial infarction and stroke (1 extra event per 133 patient-years of treatment). This increased risk only became apparent after 18 months treatment [210]. These results precipitated the withdrawal of rofecoxib [211]. The Food and Drug Administration of the USA (FDA) subsequently reviewed all available data on the cardiovascular risks of Coxibs from available clinical trials. It was concluded the data were both incomplete and did not demonstrate a consis-

Fig. 6. A summary of the known actions of NSAIDs relevant to prevention of colorectal cancer. Red arrows and blocks indicate actions of NSAIDs.

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Table 1 Randomised controlled clinical trials of Coxibs where the risk of cardiovascular complications has been reported Agent

Trial

Control agent

Increase in CV risk?

Celecoxib Celecoxib Celecoxib Celecoxib

APC [214] PreSAP [212] ADAPT [212] CLASS [215]

Yes No No No

Rofecoxib Rofexocib Valdecoxib Lumaricoxib

APPROVe [210] VIGOR [216] 2 short term studies [212] TARGET [217]

Placebo Placebo Placebo Diclofenac or Ibuprofen Placebo Naproxen Placebo

No

Etoricoxib

EDGE [212]

Naproxen or Ibuprofen Diclofenac

Yes Yes Yes

No

It should be noted that the PreSAP, ADAPT, EDGE and Valdecoxib studies have not been reported in peer review literature at the time of writing.

tent increased cardiovascular risk (Table 1). Nevertheless, as a precaution, it was recommended that Valdecoxib be withdrawn and substantial warnings of potential cardiovascular adverse reactions added to all other NSAIDs except aspirin [212]. The possible mechanism for this unexpected increased risk is not fully established but may be because of important differences in the actions of COX-1 and COX-2. In the vascular epithelium, COX-2 mediates production of PGI2 which is a vasodilator and inhibitor of platelet aggregation. Inhibition of COX-2 could leave patients exposed to the unopposed effects of thromboxane produced by COX-1 [213].

4. Conclusions The majority of genes that are functionally important in the pathogenesis of colorectal cancer in some way inactivate or raise the threshold for induction of apoptosis, giving a growth advantage to neoplastic and malignant clones. Clinical data are emerging that apoptosis in human colonic epithelium is inversely related to cancer development. Studies of mouse models are starting to illustrate how apoptosis fits in and interacts with the other important phenotypes required by cancer cells as laid out by Hahn and Weinberg [12]. When thinking of cancer prevention, apoptosis plays an important role in the protective action of fibre and other protective food constituents. Until the end of 2004, NSAIDs, and in particular Coxibs, were the most realistic candidate drugs for chemoprevention. The discovery of significant cardiovascular toxicity after long-term usage of rofecoxib and celecoxib prevents this class of agent being used in average risk populations. However, the extensive research into the potential therapeutic effects of COX-2 inhibition has not been in vain. The roles of COX and prostaglandins in colorectal carcinogenesis are now clearly defined and point to other potential targets for chemoprevention such as the prostaglandin receptors.

Reviewers Prof. Chris Paraskeva, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. Prof. E.G.E. De Vries, M.D., Ph.D., Groningen University Hospital, Department of Medical Oncology, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands. Dr. Nadir Arber, Tel Aviv Sourasky Medical Center, Weizmann 6, Tel Aviv 64238, Israel.

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Biography Alastair J.M. Watson is professor of medicine at the University of Liverpool and head of the Division of Gastroenterology in the School of Clinical Sciences. He qualified in 1980 from Cambridge and London Universities. In 1985, he became a research fellow with Michael Farthing in St. Bartholomew’s hospital from where he obtained in 1989 a Medical Doctorate on the absorption of short chain fatty acids. He became a post-doctoral fellow with Mark Donowitz and Chip Montrose at Johns Hopkins Medical School (1988–1990). He returned to the University of Manchester to work with Lord Turnberg on apoptosis in the GI epithelium. His main research interests the regulation of apoptosis in intestinal epithelium and the role of apoptosis in colorectal cancer, pancreatic disease and inflammatory bowel disease. He is on the Council of the British Society of Gastroenterology and is Deputy Editor of Gut.