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Mutations in the adenomatous polyposis coli (APC) gene are not only responsible for familial adenomatous polyposis (FAP), but also play a rate-limiting role in the majority of sporadic colorectal cancers. Colorectal tumours are known to arise through a gradual series of histological changes, the so-called ‘adenoma–carcinoma’ sequence, each accompanied by a genetic alteration in a specific oncogene or tumour suppressor gene. Loss of APC function triggers this chain of molecular and histological changes. In general, an intestinal cell needs to comply with two essential requirements to develop into a cancer: it must acquire selective advantage to allow for the initial clonal expansion, and genetic instability to allow for multiple hits at other genes responsible for tumour progression and malignant transformation. Inactivation of APC seems to fulfill both requirements. In this short review, I will discuss the role played by APC in providing, when mutated, selective advantage, through constitutional activation of the Wnt signal transduction pathway, and chromosomal instability to the nascent intestinal tumor cell. [Copyright &y& Elsevier]

Colorectal cancer still represents one of the most common causes of morbidity and mortality among Western populations. The adenomatous polyposis coli (APC) gene, originally identified as the gene responsible for familial adenomatous polyposis (FAP), an inherited predisposition to multiple colorectal tumors, is now considered as the true “gatekeeper” of colonic epithelial proliferation. It is mutated in the vast majority of sporadic colorectal tumors, and inactivation of both APC alleles occurs at early stages of tumor development in man and mouse. The study of FAP has also led to one of the most consistent genotype-phenotype correlations in hereditary cancer. However, great phenotypic variability is still observed not only among carriers of the identical APC mutation from unrelated families but also from within the same kindred. The generation of several mouse models carrying specific Apc mutations on the same inbred genetic background has confirmed the genotype-phenotype correlations initially established among FAP patients, as well as provided important insights into the mechanisms of colorectal tumor formation. Here we review the major features of the available animal models for FAP and attempt the formulation of a hypothetical model for APC-driven tumorigenesis based on the observed genetic and phenotypic variability in mouse and man. [ABSTRACT FROM AUTHOR]

Sporadic cases of colorectal cancer are primarily initiated by gene mutations in members of the canonical Wnt pathway, ultimately resulting in beta-catenin stabilisation. Nevertheless, cells displaying nuclear beta-catenin accumulation are nonrandomly distributed throughout the tumour mass and preferentially localise along the invasive front where parenchymal cells are in direct contact with the stromal microenvironment. Here, we discuss the putative role played by stromal cell types in regulating beta-catenin intracellular accumulation in a paracrine fashion. As such, the tumour microenvironment is likely to maintain the cancer stem cell phenotype in a subset of cells, thus mediating invasion and metastasis. [ABSTRACT FROM AUTHOR]

The central dogma of molecular biology states that the flow of genetic information moves from DNA to RNA to protein. However, in the last decade this dogma has been challenged by new findings on non-coding RNAs (ncRNAs) such as microRNAs (miRNAs). More recently, long non-coding RNAs (lncRNAs) have attracted much attention due to their large number and biological significance. Many lncRNAs have been identified as mapping to regulatory elements including gene promoters and enhancers, ultraconserved regions and intergenic regions of protein-coding genes. Yet, the biological function and molecular mechanisms of lncRNA in human diseases in general and cancer in particular remain largely unknown. Data from the literature suggest that lncRNA, often via interaction with proteins, functions in specific genomic loci or use their own transcription loci for regulatory activity. In this review, we summarize recent findings supporting the importance of DNA loci in lncRNA function and the underlying molecular mechanisms via cis or trans regulation, and discuss their implications in cancer. In addition, we use the 8q24 genomic locus, a region containing interactive SNPs, DNA regulatory elements and lncRNAs, as an example to illustrate how single-nucleotide polymorphism (SNP) located within lncRNAs may be functionally associated with the individual's susceptibility to cancer. [ABSTRACT FROM AUTHOR]

Background:The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.Methods:Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998-2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.Results:In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63-0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50-0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46-0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79-1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70-2.20; P<0.001).Conclusion:Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients. [ABSTRACT FROM AUTHOR]

Summary: Long-standing ulcerative colitis (UC) has been associated with a high risk of developing colonic adenocarcinoma. Importantly, both low- and high-grade dysplasia are strongly related to the presence or development of malignancy. The canonical Wnt/β-catenin signaling pathway is of crucial importance in cancer development and progression, but its role in UC-related carcinogenesis remains to be determined. We evaluated the immunolabeling patterns of β-catenin, as well as the products of Wnt-associated cancer genes E-cadherin, cyclin D1 and c-myc, along the dysplasia–carcinoma pathway in UC. For this purpose, immunohistochemistry (IHC) was performed on 18 adenocarcinomas and 17 dysplasias, derived from 21 patients. We found that intracellular β-catenin accumulation, the hallmark of Wnt signaling activation, is observed in dysplasia, together with enhanced labeling of nuclear protein cyclin D1 and reduction of membranous labeling of E-cadherin. c-myc displayed moderate immunolabeling in the (pre)malignant lesions. Thus, the Wnt pathway is activated in early stages of malignant progression in UC. Furthermore, upregulation of the oncogene cyclin D1 and downregulation of tumor suppressor E-cadherin also occurs in the (pre)neoplastic state. This may contribute to the high potential for malignant degeneration of dysplasia in UC-related colitis. [Copyright &y& Elsevier]

Abstract: Colorectal cancer still represents a paradigm for the elucidation of the cellular, genetic and molecular mechanisms that underly solid tumor initiation, progression to malignancy, and metastasis to distal organ sites. The relative ease with which pathological specimens can be obtained by either surgery or endoscopy from different stages of tumor progression has facilitated the application of omics technologies to allow the genome-wide analysis both at the RNA (gene expression) and DNA (aneuploidy) levels. Here, we have reviewed the multiplicity of studies appeared to date in the scientific literature on the expression and genomic analysis of colorectal cancer, and attempted an integration of the profiling data generated and made available in the public domain. This approach is likely to pinpoint specific chromosomal loci and the corresponding genes which (i) play rate-limiting roles in colorectal cancer, (ii) represent putative diagnostic and prognostic markers for the accurate prediction of clinical outcome and response to treatment, and (iii) encompass potential therapeutic targets. Moreover, cross-species data mining and integration of the human colorectal cancer profiles with those obtained from mouse models of intestinal tumorigenesis will even more contribute to the elucidation of highly conserved pathways and cellular functions underlying malignancy in the GI tract. Notwithstanding the above promises, tumor heterogeneity, limited cohort sizes, and methodological differences among experimental and bioinformatic approaches still poses main obstacles towards the optimal utilization and integration of omics profiles. [Copyright &y& Elsevier]

The Smad4+/E6sad mouse carries a null mutation in the endogenous Smad4 gene resulting in serrated adenomas and mixed polyposis of the upper gastrointestinal (GI) tract with 100% penetrance. Here, we show by loss of heterozygosity (LOH) analysis and immunohistochemistry (IHC) that, although the majority of the tumors appear at 9 months of age, somatic loss of the wild-type Smad4 allele occurs only at later stages of tumor progression. Hence, haploinsufficiency underlies Smad4-driven tumor initiation in the GI tract. As both the Apc and Smad4 tumor suppressor genes map to mouse chromosome 18, we have bred Smad4+/E6sad with the Apc+/1638N model to generate two distinct compound heterozygous lines carrying both mutations either in cis (CAS) or in trans (TAS). Strikingly, both models show increased tumor multiplicities when compared with the single mutant littermates, although CAS mice are more severely affected and became moribund at only 5–6 weeks of age. Phenotypic and molecular analyses indicate that Smad4 haploinsufficiency is sufficient to significantly affect tumor initiation and progression both prior to and upon loss of Apc function. Moreover, complete loss of Smad4 strongly enhances Apc-driven tumor formation.Oncogene (2006) 25, 1841–1851. doi:10.1038/sj.onc.1209226; published online 14 November 2005 [ABSTRACT FROM AUTHOR]

The role of Msh2 in chromosome stability has been investigated in a targeted mouse model for HNPCC, Msh2Δ7N. Chromosome aberration frequencies were similar in bone marrow of Msh2[SUP+/+], Msh2[SUP+/-] and Msh2[SUP-/-] mice and no differential effects of in vivo X-irradiation were noted. By contrast, the induction of sister-chromatid exchanges (SCEs) by methyl nitrosourea (MNU) was reduced in Msh2[SUP-/-] and Msh2[SUP+/-] cells to ∼20% and ∼45% wild-type levels respectively indicating a phenotypic effect of haploinsufficiency of the mouse Msh2 gene. [ABSTRACT FROM AUTHOR]

SUMMARY Recently, a mouse model for Barrett's esophagus based on a zinc-deficient diet supplemented with deoxycholic bile acids has been published. The aim of this study was to attempt to reproduce these data and extend them by employing genetically modified mice and intraperitoneal iron supplementation. The study design encompassed six experimental groups (wild type, Apc-mutant and Smad4-mutant mice, with or without iron injections), with all animals fed with the zinc-deficient diet supplemented with deoxycholic bile acids. All treatments were started at 3-5 weeks of age (the majority [78%] at 5 weeks). Animals were scheduled for euthanasia at two distinct time points, namely at 3 and 6 months of age. All mice showed signs of considerable distress already 4 weeks after the start of the modified diets, and had to be euthanized before the first evaluation time point (mean age 9.3 weeks, range 5-15 weeks). No differences were observed between wild type and genetically modified mice, or between animals with or without iron supplementation. On histological examination, we could not detect any lesions (Barrett's esophagus-like or tumors) other than esophagitis. In the currently presented experimental settings, we were not able to reproduce the mouse model according to which Barrett's-like lesions could be detected in animals fed with the zinc-deficient diet supplemented with deoxycholic bile acids. [ABSTRACT FROM AUTHOR]

Presents a corrected version of two articles appearing in previous issues of the journal 'Nature Genetics.'

Presents a letter to the editor of the journal 'Cell Death and Differentiation' regarding Marfanoid habitus and FAP characterized by an interstitial deletion of chromosome 5q not encompassing the fibrillin 2 gene. Detection of a point mutation in the donor splice of exon 4 of the APC gene; Ruling out of a gross deletion or rearrangement involving the nearby 2 gene locus on 5q23-31.