A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts

Leedham, Simon J.; Rodenas-Cuadrado, Pedro; Howarth, Kimberley; Lewis, Annabelle; Mallappa, Sreelakshmi; Segditsas, Stefania; Belnoue-Davis, Hayley L.; Jeffery, Rosemary; Rodriguez‐Justo, Manuel; Keshav, Satish; Travis, Simon; Graham, Trevor A.; East, James E.; Clark, Susan; Tomlinson, Ian

doi:10.1136/gutjnl-2011-301601

Cited by 85 publications

(95 citation statements)

References 32 publications

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“…The principal comparison was to test our hypothesis that the R482Q allele occurs commonly in human tumours because it provides a greater level of functional derangement than a single null Fbxw7 allele. On an Apc mutant background, polyposis developed more rapidly in R482Q than Fbxw7 +/− animals, and there was additionally a relative shift in polyp numbers to SB1, a feature previously associated with more severe disease 27 30 – 32…”

Section: Discussionmentioning

confidence: 94%

Investigation of the atypicalFBXW7mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

Belnoue-Davis

Lewis

Behrens

et al. 2013

Gut

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ObjectiveFBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at β-propellor tips involved in substrate recognition.DesignFBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a Fbxw7fl(R482Q)/+ mouse and conditionally expressed this mutation in the intestines using Vill-Cre. We compared these mice with heterozygous null (Fbxw7+/−) mutants.ResultsA few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and Fbxw7+/− mice at age >300 days. Breeding the R482Q allele onto Apc mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and Fbxw7−/− mice, but not Fbxw7+/− animals. On the Apc mutant background, Fbxw7+/− mutants had a phenotype intermediate between Fbxw7 wild-type and R482Q/+ mice.ConclusionsHeterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null Fbxw7 mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the FBXW7 mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease.

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Section: Discussionmentioning

confidence: 94%

Investigation of the atypicalFBXW7mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

Belnoue-Davis

Lewis

Behrens

et al. 2013

Gut

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“…However, there are substantial differences in physiology of the various parts of the intestine, such as cell proliferation rate and cell type composition [39], stem cell density, and basal levels of the Wnt signaling [40]. These differences have a particular clinical relevance, since development of intestinal cancer in humans is predominantly constrained to the large bowel.…”

Section: Brg1 Loss Is Compensated By Brm Upregulation In Large Intestmentioning

confidence: 99%

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

et al. 2013

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Brg1 is a chromatin remodeling factor involved in mediation of a plethora of signaling pathways leading to its participation in various physiological processes both during development and in adult tissues. Among other signaling pathways, the Wnt pathway has been proposed to require Brg1 for transactivation of its target genes. Given the pivotal role of the Wnt pathway in the maintenance of normal intestinal homeostasis, we aimed to investigate the effects of Brg1 loss on the intestinal physiology. To this end, we deleted Brg1 in the murine small and large intestinal epithelia using a range of transgenic approaches. Pan-epithelial loss of Brg1 in the small intestine resulted in crypt ablation, while partial Brg1 deficiency led to gradual repopulation of the intestinal mucosa with wild-type cells. In contrast, Brg1 loss in the large intestinal epithelium was compensated by upregulation of Brm. We propose that while Brg1 is dispensable for the survival and function of the progenitor and differentiated cells in the murine intestinal epithelium, it is essential for the maintenance of the stem cell population in a tissuespecific manner.

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“…10, 11). In the just right model, the tumorigenic optimum may vary with microenvironment, such as tumor location or the stage of tumorigenesis, and in the case of adenomatous polyposis coli (APC) there is substantial experimental evidence to support this (12,13). The fail-safe nomenclature implies the existence of an inherent antitumor component.…”

Section: Critique Of the Modelmentioning

confidence: 99%

The Continuum Model of Selection in Human Tumors: General Paradigm or Niche Product?

Leedham

Tomlinson²

2012

Cancer Research

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Berger and colleagues recently proposed a continuum model of how somatic mutations cause tumors to grow, thus supplementing the established binary models, such as oncogene activation and "two hits" at tumor suppressor loci. In the basic continuum model, decreases or increases in gene function, short of full inactivation or activation, impact linearly on cancer development. An extension, called the fail-safe model, envisaged an optimum level of gene derangement for tumor growth, but proposed that the cell gained protection from tumorigenesis because additional mutations caused excessive derangement. Most of the evidence in support of the continuum model came from Pten mutant mice rather than humans. In this article, we assess the validity and applicability of the continuum and fail-safe models. We suggest that the latter is of limited use: In part, it restates the existing "just right" of optimum intermediate gene derangement in tumorigenesis, and in part it is inherently implausible that a cell should avoid becoming cancerous only when it is some way down the road to that state. In contrast, the basic continuum model is a very useful addition to the other genetic models of tumorigenesis, especially in certain scenarios. Fittingly for a quantitative model, we propose that the continuum model is most likely to apply where multiple, cancer-promoting mutations have relatively small, additive effects, either through the well-established case of additive germline predisposition alleles or in a largely hypothetical situation where cancers may have acquired several somatic "mini-driver" mutations, each with weaker effects than classical tumor suppressors or fully activated oncogenes. Cancer Res; 72(13);

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A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts

Cited by 85 publications

References 32 publications

Investigation of the atypicalFBXW7mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

Investigation of the atypicalFBXW7mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines

Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

The Continuum Model of Selection in Human Tumors: General Paradigm or Niche Product?

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