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British Medical Bulletin 64:45-58 (2002)
© 2002 Oxford University Press

Genetics – cellular basis

Advances in colorectal cancer

Andrea Buda and Massimo Pignatelli

Division of Histopathology, Department of Pathology and Microbiology, Bristol Royal Infirmary, Bristol, UK


   Abstract
Top
 Footnotes
 Abstract
The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 
Colorectal carcinogenesis is a multistep process during which the specialised epithelial cells of intestinal mucosa surface (e.g. colonocytes) accumulate a series of genetic and epigenetic events which lead to a perturbation of their normal cellular functions and turnover. This review will address the mechanisms and biological effects of these abnormalities on the growth control, differentiation, adhesion and survival of the colonocytes.


   The APC/ß-catenin pathway
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 
Although several oncogenes and oncosuppressor genes are known to be involved in colorectal carcinogenesis, mutation of the adenomatous polyposis coli (APC) gene and the components of the ß-catenin pathways are particularly crucial in the promotion of this process.

Mutation of APC represents a crucial event in colorectal carcinogenesis1Go,2Go. Loss of function of the APC gene is found in up to 85% of all hereditary and sporadic colon cancers. Mutations in the APC gene occur early during tumour formation and a growing body of evidence support the role of APC as a gatekeeper gene in colorectal carcinogenesis3Go. The APC gene encodes a large intracellular protein that has a central role in the regulation of epithelial cell adhesion and cellular transcription. Multiple functional domains mediate both oligomerization and binding to many intracellular proteins including ß- and {gamma}-catenin, glycogen synthase kinase (GSK)-3ß, Axin, tubulin, EB1 and hDLG. These interactions are responsible for APC-mediated cell–cell adhesion, stability of the microtubular cytoskeleton, cell cycle regulation and apoptosis.

The discovery that APC protein binds to cytosolic ß-catenin has given an important insight into the understanding of the biological function of APC in colorectal cancer4Go. It is commonly accepted that the key tumour suppressor function of APC lies on its ability to regulate the stability and cellular localisation of ß-catenin5Go. This protein was first described in humans as a member of the cell membrane-bound adherens complex. Subsequent comparative studies of signalling pathways in Xenopus and Drosophila have shown that ß-catenin represents an essential component of the Wnt pathway (see below). A schematic summary of established ß-catenin pathways is shown in Figure 1. ß-Catenin may be regarded as existing in three different subcellular forms6Go: membrane bound as a part of the adherens junction complex, cytosolic, and nuclear. When is dissociated from the other components of the adherens complex (e.g. epithelial-cadherin, {alpha}-catenin), ß-catenin is transferred to the cytosol where it may be degraded or translocated to the nucleus7Go. The degradation of ß-catenin involves binding of the protein to a complex constituted by APC protein, GSK-3ß and Axin. GSK-3ß serves to phosphorylate serine and threonine residues on ß-catenin, a crucial step required to target the protein for ubiquitination and proteosomal degradation8Go. Phosphorylation of ß-catenin enables binding to the F box protein ß-transducing repeat-containing protein (ß-TrCP) and, therefore, the ubiquitin-mediated proteolysis9Go. Axin has a scaffold function and its interaction with GSK-3ß and APC promotes the phosphorylation of ß-catenin.



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  		Fig. 1 Schematic representation of ß-catenin pathways. ß-Catenin binds to E-cadherin and via {alpha}-catenin to the actin cytoskeleton to form adherens junctions. Unbound cytoplasmic ß-catenin is sequestered in a complex including APC, AXIN and GSK-3ß which phosphorylate (P) ß-catenin. ß-TrCP together with E1 and E2 ubiquitination components, mediate ß-catenin ubiquitination and degradation by proteosomes. In response to Wnt, Dvl antagonises ß-catenin phosphorylation leading to increased level of free cytoplasmic ß-catenin. Stabilised ß-catenin is translocated into the nucleus where it binds with transcription factors (Lef/Tcf) and stimulates transcription of target genes. Frz, Frizzled receptor; Dvl, dishevelled; GSK, glycogen synthase kinase-3ß; APC, adenomatous polyposis coli; ß-TrCP, ß transducing repeat containing protein.

 
Most of the mutations of APC involve the central region of the APC gene referred to as the mutation cluster region (MCR). Mutation of the MCR results in a truncated APC protein that lacks the Axin binding site and the 20 amino acid repeat which is essential for ß-catenin binding. Loss of APC protein binding significantly reduces phosphorylation of ß-catenin by GSK-3ß, leading to an accumulation of nuclear ß-catenin, a feature associated with progression along the adenoma-carcinoma sequence10Go. Immunohistochemical studies have shown distinct ß-catenin subcellular patterns in colorectal carcinomas, adenomas and non-neoplastic epithelium. ß-Catenin is expressed in the cytoplasm and in the nucleus in adenomas and carcinomas whereas in benign tissue it is mainly membranous. Nuclear ß-catenin localisation strongly correlates with tumour size and dysplasia, and high levels of nuclear expression have been found at invasion fronts of adenocarcinomas11Go. Several studies have investigated the correlation between ß-catenin localisation and clinical outcome in colorectal cancer, and showed that wide-spread nuclear and cytoplasmic localisation were independently predictive of shorter survival and hematogenous metastasis12Go,13Go. Mutations of ß-catenin itself have been shown to contribute to its nuclear accumulation. The most common mutations that have been found in the human gene encoding ß-catenin (CTNNB1) affect the protein's serine and threonine residues that are targeted by GSK-3ß. As a result, the mutant protein is resistant to phosphorylation and escapes ubiquitination/proteosomal degradation. Alterations of the ß-catenin gene are found in various neoplasms such as childhood hepatoblastoma (48%), prostate cancer (5%), endometrial carcinoma (14%), and anaplastic thyroid carcinoma (6%). Overall, ß-catenin mutations have been found in 4–15% of all sporadic colorectal adenomas and carcinomas. ß-Catenin mutation could play an important role in colorectal cancer with wild-type APC. Indeed, a recent study showed that CTNNB1 mutations have been identified in as many as 50% of colorectal cancers lacking APC mutations5Go. In the same series, APC and CTNNB1 mutation were mutually exclusive although they have been previously described in the same colorectal cancer line14Go. Fundic gland polyps (FGPs) are the most common gastric polyp. FGPs occur sporadically or in association with familial adenomatous polyposis (FAP) syndrome that harbours somatic gene alteration of the APC gene. In sporadic FGPs, APC mutation is less common and two recent studies have shown ß-catenin mutation in more than 80% of these in tumours15Go,16Go. Because sporadic FGPs are non-neoplastic lesions whereas FGPs associated with FAP frequently show dysplasia, ß-catenin mutation appears to have a weaker oncogenic potential. In keeping with these findings, ß-catenin mutations are more frequent in small adenomas compared to large adenomas and/or carcinomas17Go. Colorectal cancers associated with ulcerative colitis do not usually develop from adenomas suggesting a different genetic pathway from sporadic cancers. The role of the APC/ß-catenin pathway is not completely clear since mutation in APC appears to be a rare event in UC-related cancers18Go. However, abnormal APC and ß catenin expression and cellular localisation have been found in approximately 80% of UC-related tumours, with a decreased cytoplasmic staining for APC coupled with an increased cytoplasmic and nuclear localisation of ß-catenin19Go. An important regulator of the ß-catenin pathway is the Wingless/Wnt signalling pathway which will be discussed below.


   APC and migration
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
 APC and migration
E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 
Recent findings have highlighted another important functional aspect of APC related to its subcellular localisation. APC has been found at the sites of cell–cell adhesion in various epithelial cells along the lateral membrane. In vitro and in vivo experiments have shown that APC bind directly to microtubules20Go,21Go. Although microtubule organisation through the ‘search and capture’ mechanism is essential during mitosis and varies considerably during the different stages of the cell cycle, the association with APC could play an important role in cell migration22Go. During the wound-healing process of Xenopus epithelial cells, Mimori-Kiyosue and colleagues found that APC gradually concentrate at the distal end of a subset of microtubules, growing towards the wounded region23Go. The relationship between APC and the actin-based cytoskeleton has also been investigated. In MDCK cells, APC were shown to increase Rac activation followed by actin polymerisation at the cell periphery, resulting in ruffling and lamellopodia formation24Go. APC mutation could be involved in polyp formation not only influencing proliferation and differentiation, but also the migration and adhesion of the epithelial cell through its association with the cytoskeleton. Mutation of the APC gene may induce a defect in the migration and maturation of intestinal epithelial cells with an aberrant expansion of the proliferative zone and possible accumulation of other genetic events.


   E-cadherin/ß-catenin complex
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 
Decrease in cellular adhesion, loss of contact inhibition, increase in proliferation and de-differentiation are observed in the progression of tumours to an invasive phenotype. Cadherins are a large family of transmembrane glycoproteins which represent the prime mediators of calcium-dependent, cell-to-cell adhesion in normal epithelial cells. Epithelial (E) cadherin forms the key functional component of adherens junctions of all epithelial cells and plays a major part in the establishment and maintenance of cell polarity and tissue architecture25Go. Translation of intercellular contact signals into cellular organisation is mediated by catenins. Catenins {alpha}-, ß- and {gamma}- are membrane undercoat proteins that link the cytoplasmic terminal tail of E-cadherin to the actin cytoskeleton. Of these, ß-catenin and {gamma}-catenin bind directly to the cytoplasmic tail of E-cadherin whereas {alpha}-catenin links the bound ß-catenin to the actin microfilament network of the cellular cytoskeleton. An intact E-cadherin–catenin complex is required for maintenance of normal intercellular adhesion26Go.

In carcinomas, E-cadherin functions as an invasion suppressor molecule such that its loss permits or enhances the invasion of adjacent normal tissues. In vitro studies have shown that reconstruction of cadherin binding in human carcinoma cell lines by transfection with E-cadherin cDNA results in a more differentiated phenotype and loss of invasiveness27Go. Furthermore, colonic carcinoma cell lines acquire a de-differentiated and invasive behaviour when intercellular adhesion is inhibited by anti-E-cadherin monoclonal antibodies28Go. Indeed, results from clinical studies have shown that, in colorectal cancer, loss of differentiation and increased invasiveness are associated with loss of expression and function of E-cadherin29Go. These observations clearly demonstrate that E-cadherin acts as an ‘invasion-suppressor’ gene. However, it remains unsolved whether the loss of E-cadherin/catenin cell adhesion is a prerequisite for tumour progression or is a consequence of de-differentiation during cancer progression in vivo. Using a transgenic mouse model of pancreatic ß-cell tumorigenesis, Perl and colleagues demonstrated that loss of E-cadherin has a casual role in the transition from adenoma to carcinoma30Go.

Mutations of the E-cadherin gene (CDH1) have been described in several epithelial cancers, including breast, stomach, endometrium, ovary and thyroid. Inactivating mutations are commonly found in two histological subtypes of poorly cohesive tumours, namely lobular breast and diffuse-type gastric carcinoma31Go. In colorectal cancer, inactivation of CDH1 is not a common event although is relatively frequent in the subset with replication error phenotype. The fact that E-cadherin expression and function is often perturbed in colorectal cancer suggests that other non-mutational mechanisms are involved.

Epigenetic events are alternative mechanisms of gene modulation affecting the expression of a gene without disrupting its sequence. DNA methylation is recognised as a key epigenetic mechanism and recently its role in colorectal cancer development has become increasingly clear. Wheeler and colleagues have recently shown hypermethylation of the promoter region of the E-cadherin gene in about 50% of colorectal cancer and this was significantly associated with reduced or absent expression of E-cadherin protein32Go.

Thus, inactivation of E-cadherin by genetic and epigenetic events may play a key role in both the early and later stages of multistep carcinogenesis. E-cadherin is also important for the negative control of cell-growth. One proposed mechanism involves the ability of E-cadherin to inhibit cell proliferation by the up-regulation of the cyclin-dependent kinase inhibitor (cdk) p2733Go. p27 regulates progression from G1 into S phase by binding and inhibiting the cyclin E/cdk2 complex which is required for cells to enter S phase. Transfection of E-cadherin into E-cadherin negative mammary carcinoma cells caused an increase in cell aggregation and reduced proliferation coupled to increased expression of p27. Reduced p27 expression has been also found to correlate with poor survival and increased risk for lymph node metastasis in patients with colorectal cancer.

The role of down-regulation of E-cadherin expression and functional activity in tumour progression and metastasis of colorectal cancer is not only related to loss of cell-to-cell adhesion but also to loss of suppression of nuclear ß-catenin activity. Disruption of the E-cadherin/ß-catenin complex releases ß-catenin from the membranous pool: when not rapidly degraded, ß-catenin can translocate into the nucleus inducing the transcription of genes involved in tumour invasion. In colorectal cancers, the central part of the tumour still displays high levels of E-cadherin at the cell membrane, co-localised with ß-catenin. In contrast, at the invasive front, ß-catenin is localised mainly in the nuclei of dissociated cancer cells that have lost E-cadherin expression. The loss of E-cadherin in such cells seems to be reversible and regulated by the tumour environment, since metastatic nodes exhibit normal E-cadherin expression34Go. Thus, during the process of invasion and metastasis, inactivation of E-cadherin intercellular adhesion triggers the release of cancer cells from the primary tumour and the subsequent translocation of ß-catenin induces expression of genes that promote invasion and proliferation in the target organ35Go.

As with E-cadherin, loss of {alpha}-catenin is frequently described in colorectal cancer and may be important in releasing ß-catenin from the membrane-bound state. Gofuku and colleagues examined the expression of {alpha}-catenin and E-cadherin in 100 tissue samples from patients undergoing resection of colorectal cancer and found that {alpha}-catenin was reduced in 56% of the patients36Go. Low expression correlated with depth of tumour invasion, the presence of liver and lymph node metastasis and Dukes' stage. In contrast, E-cadherin expression was reduced in 29% of the patients but did not correlate with patients' survival.

In some colorectal cancers, the staining pattern of the E-cadherin/catenin complex does not always show an absent or reduced expression, but only redistribution from cell membrane to the cytoplasm. Failure of the E-cadherin/catenin complex to localise to the membrane and/or bind to the cytoskeleton in spite of normal expression may be due to post-transcriptional modification of the complex. For example, epidermal growth factor (EGF) and hepatocyte growth factor (HGF) have been shown to promote tyrosine phosphorylation of ß-catenin and, hence, disruption of the adhesion complex. It is uncertain whether this phosphorylation is performed by the growth factor receptors themselves or via soluble tyrosine kinases. Mutations of the ras oncogene and the presence of cytoplasmic expression of the trefoil peptide TTF-3 are frequently observed in colorectal cancers. Inducing overexpression of ras oncogene or treatment with TTF-3 promote tyrosine phosphorylation of ß-catenin in vitro37Go,38Go. However, in the case of TTF-3 treatment, tyrosine phosphorylation of ß-catenin was not associated with an increased nuclear accumulation and it is possible that additional factors are needed for the translocation of the membrane-released ß-catenin.


   Wingless/Wnt signalling pathway
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
Transforming growth factor beta...
 References
 
The Wnt pathway plays a key role during normal mammalian development and its abnormal activation is associated with malignant transformation. It is now believed that transformation of adult mammalian cells into malignant tumour reflects, at least in some cancers, an abnormal activation of this pathway39Go. When Wnt ligands bind their transmembrane receptor Frizzled, the cytoplasmic protein Dishevelled is recruited to the membrane and inactivates the multiprotein complex that marks free cytoplasmic ß-catenin for degradation40Go,41Go. Free cytoplasmic ß-catenin is translocated to the nucleus where it binds with a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to form a complex that activates transcription of target genes by binding to their promoter sequence42Go. Of this family of transcription factors, TCF-4 has the most relevance in colorectal carcinogenesis. In vivo studies have shown that TCF-4 is required for the maintenance of the undifferentiated cycling crypt cell compartment43Go. Increased levels of stabilised cytoplasmic ß-catenin, as a result of mutation in APC or in other genes involved in the Wnt pathway, could be responsible for the inappropriate activation of TCF-4 and expansion of the crypt compartment44Go.

Another deregulation of the Wnt signalling pathway could be achieved by mutation of Axin gene. There are two Axin gene family members that have been isolated in man: Axin1 and Axin2. As described above, the protein Axin functions by promoting degradation of ß-catenin. Satoh and colleagues have recently described non-sense mutation of the Axin1 gene in hepatocellular carcinomas45Go. These mutations produced a truncated Axin protein with reduced binding to ß-catenin and was associated with nuclear accumulation of ß-catenin and increased ß-catenin/TCF transcriptional activity. Liu and colleagues46Go demonstrated that frame-shift mutation of Axin2 in 11 out of 45 colorectal cancers showing microsatellite instability, compared with none of 60 microsatellite stable tumours. The fact that Axin is one of the target genes in colorectal cancers with microsatellite instability has been recently confirmed by Shimizu and colleagues who found mutation of Axin1 in the APC-binding and GSK-3ß-binding domains in 21% of colorectal cancers with microsatellite instability47Go. Axin acts as a negative regulator within the Wnt-signalling pathway and is crucial for ß-catenin degradation. Axin–APC interaction promotes the phosphorylation of APC itself by GSK-3ß and the phosphorylated form of APC seems to induce the degradation of ß-catenin more than the unphosphorylated one. Thus, the reduced capacity of Axin to form a complex with APC results in accumulation and transcriptional activation of ß-catenin45Go.

ß-Catenin/TCF activity up-regulates genes critical for proliferation and malignant transformation of colonic epithelial cells such as c-Myc, cyclin D1, gastrin and a variety of other genes that contribute to cancer progression. These include the extracellular matrix protein fibronectin, involved in cell adhesion and motility, the metalloproteinase matrilysin (MMP-7) and the urokinase-type plasminogen activator receptor (uPAR)48Go. MMP-7 is expressed in up to 90% of colorectal cancers and is thought to be important in mediating stromal invasion49Go, although recently it has been suggested that may also have a role in earlier stages of carcinogenesis. Ablation of MMP-7 expression reduces the number of intestinal adenomas in multiple intestinal neoplasia (Min) mice, a model of FAP50Go. Another factor that mediates stromal invasion in colorectal cancer is the proteolytic protein plasmin, which is produced by cleavage of plasminogen51Go. The uPAR is functionally involved in this process and is overexpressed at the invasion front of colorectal cancers52Go. Another gene that has been found to be a novel target of the Wnt pathway in colon cancer is the gene for vascular endothelial growth factor (VEGF)53Go. VEGF is a key regulator of tumour angiogenesis and, in colon cancer, high levels correlate with poor clinical outcome. Angiogenesis is not restricted to advanced stages of cancer, but can also be observed in premalignant lesions like colorectal adenomas, where VEGF protein and RNA levels are increased compared to normal mucosa. Zhang and colleagues found that Wnt signalling strongly up-regulated VEGF through a TCF-4 binding element in the promoter region of the gene53Go. In the same study, K-ras, another gene involved in the adenoma-carcinoma sequence, was demonstrated to interact with Wnt to up-regulate VEGF, providing a molecular basis for the angiogenesis observed in benign colonic adenomas.

There has been recent interest in possible roles for two mammalian homologues of the Drosophila caudal homeobox gene, Cdx1 and Cdx2, in colorectal carcinogenesis. These homeobox genes participate in the control of intestinal homeostasis by regulating the balance between proliferation and differentiation during the renewal of the intestinal epithelium. In the intestinal epithelium, Cdx1 is expressed in the intestinal crypts and stimulates proliferation whereas Cdx2 is expressed in differentiated cells and reduces proliferation. Cdx1 overexpression increases cell proliferation and inhibits apoptosis in vitro, whereas transgenic mice heterozygous for a null Cdx2 mutation develop gastrointestinal adenomatous polyps, particularly in the proximal colon. It has been shown that CDX1 and CDX2 interact with the Wnt/ß-catenin/Tcf pathway. Wnt signalling promotes CDX1 expression during the normal process of development in mammals. Cdx1 promoter has a binding site for the ß-catenin/TCF complex and TCF-4 knockout mice showed reduced intestinal expression of CDX254Go. Recently, Domon-Dell and colleagues have demonstrated that the oncogenic activation of the ß-catenin/TCF pathway stimulates Cdx1 expression in colorectal cancer cells whereas CDX2 exerts an inhibitory effect on the basal and ß-catenin-stimulated activity of the Cdx1 promoter55Go.

Disregulation of apoptosis plays an important role in colorectal carcinogenesis56Go. Nuclear ß-catenin signalling seems to have an anti-apoptotic effect in that mechanisms that reduce such signalling (e.g. introduction of functioning APC or Axin protein) also induce apoptosis. A possible explanation involves the multidrug resistance-1 (Mdr-1) gene and its product P-glycoprotein (Pgp), another target of nuclear ß-catenin signalling. Pgp is thought to have a generic anti-apoptotic function and, in keeping with this, Pgp expression in colorectal cancer has been shown to correlate with markers of a more aggressive phenotype such as vascular invasion, lymph node metastases and shorter disease-free survival57Go. Mdr-1 promoter activity seems to be directly regulated by TCF-4 and a close correlation between Pgp expression and accumulation of ß-catenin was demonstrated in colorectal adenomas and carcinomas from patients with FAP. Although the mutation of the p53 gene and the loss of the pro-apoptotic function of its protein product is undoubtedly important in the progression of colorectal tumours, there have been surprisingly few studies on the possible relationship with the ß-catenin signalling pathway. One study showed that overexpression of nuclear ß-catenin in lung adenocarcinoma cell lines led to accumulation of transcriptionally active p53 probably through inhibition of its degradation58Go. These results are in contrast with the previously mentioned anti-apoptotic effect of ß-catenin signalling and, therefore, it will be important to see whether they can be reproduced in colorectal cancer cell lines. However, recent data suggest that p53 may in turn reduced ß-catenin expression through a pathway independent of both GSK-3ß phosphorylation and ß-TrCP proteolysis, namely by inducing ß-catenin Siah-mediated degradation59Go. Mutational loss of p53 function could lead to a failure of Siah-mediated ß-catenin down-regulation and co-operate with other components of the Wnt pathway, providing another mechanism by which loss of p53 function promotes colorectal carcinogenesis.


   Transforming growth factor beta (TGF-ß) pathway
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
References
 
Alteration of TGF-ß signalling pathways is involved in a wide variety of human diseases, including inflammatory diseases, autoimmune diseases and cancers.

TGF-ß signalling pathway is composed of TGF-ß type I (TßRI) and II (TßRII) receptors and Smad proteins. When the ligand binds TßRII, a heteromeric complex with TßRI is formed resulting in TßRI phosphorylation. Cytoplasmic Smad2 and Smad3 are important substrates for the activated TßRI. After phosphorylation by TßRI, Smad2 and Smad3 bind in a heterotrimeric complex with Smad4 and translocate into the nucleus and activate the transcription of specific target genes. The induction of the Cdk inhibitors p15 and p21 represents a central event in the growth-inhibitory effects of TGF-ß. In intestinal epithelium, TGF-ß has an antiproliferative role inducing growth arrest in the late G1 phase of the cell cycle and apoptosis60Go,61Go. Both TGF-ß and TGF-ßII receptor increase from the proliferative compartment to the top of the crypt62Go, inversely correlated with the mitotic activity. Loss of normal growth inhibitory response to TGF-ß is involved in the transformation from a normal to a malignant phenotype and a decreased response to this inhibitory effect was found associated with a conversion of adenoma to a tumorigenic adenocarcinoma in vitro63Go. Down-regulation or mutation of TßRII appear to contribute to the development of resistance to the growth inhibitory action of TGF-ß. The activation of Ras protein, frequently found in colorectal cancer, results in a decreased expression of TßRII64Go which was also observed in adenomatous epithelium in the Min mouse model65Go. Inactivation of TßRII gene is frequent in colorectal cancers with microsatellite instability or replication error phenotype61Go,66Go. Disruption of Smad signalling seems also to be involved in pathogenesis and evolution of colorectal cancer. Inactivation of Smad4 has been associated with late stage or metastatic colorectal cancer and constitutional mutation can cause juvenile polyposis syndrome, a disorder characterised by the presence of hamartomatous polyps with a significant increased risk of malignant transformation67Go. These types of mutation may result in cancers with a different phenotype compared to that with loss of TßRII and could explain a portion of TGF-ß resistant tumour with normal type II receptor.

Although they are quite distinct, several studies have described an interaction between downstream effectors of the TGF-ß and the Wnt signalling pathways during developmental events. A direct physical interaction between Smad4 and the ß-catenin/TCF complex has been shown in Xenopus embryos68Go and a co-operation between TGF-ß and the Wnt pathways in the regulation of specific genes has been demonstrated in vitro69Go. As mentioned, both pathways are involved in tumour development and progression, but the biological importance of this interaction in colonic carcinogenesis still needs to be determined.


   Footnotes
Top
 Footnotes
Abstract
 The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 
Correspondence to: Prof. Massimo Pignatelli, Division of Histopathology, Department of Pathology and Microbiology, Bristol Royal Infirmary, Bristol BS2 8HW, UK


   References
Top
 Footnotes
 Abstract
 The APC/ß-catenin...
 APC and migration
 E-cadherin/ß-catenin...
 Wingless/Wnt signalling pathway
 Transforming growth factor beta...
 References
 

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