The Pleiotropic Phenotype of <i>Apc</i> Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

Halberg, Richard B.; Chen, Xiaodi; Amos‐Landgraf, James; White, Alanna; Rasmussen, Kristin; Clipson, Linda; Pasch, Cheri A.; Sullivan, Ruth; Pitot, Henry C.; Dove, William F.

doi:10.1534/genetics.108.091967

Cited by 13 publications

(8 citation statements)

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“…These lesions were characterized as ductal carcinoma in situ with features similar to human PanINs, IPMN and MCN. We hypothesized that changing the genetic background may affect the neoplastic phenotype as several studies have demonstrated that genetic background may affect the phenotype of transgenic mice 12, 13. We demonstrated that the incidence of pancreatic neoplasia in EL‐Kras FVB mice at 8‐10 months of age was zero percent compared to 92% in age‐matched EL‐Kras F1 mice (12 mice per group) (Fig.…”

Section: Resultsmentioning

confidence: 78%

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Alteration of strain background and a high omega‐6 fat diet induces earlier onset of pancreatic neoplasia in EL‐Kras transgenic mice

Cheon

Strouch

Barron

et al. 2010

Intl Journal of Cancer

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Diets containing omega-6 (x-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of x-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in x-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras G12D (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high x-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in x-6 fatty acid.Pancreatic adenocarcinoma is the fourth leading cause of cancer-related mortality in the U.S. 1 An estimated 34,290 deaths resulted from pancreatic cancer in 2008 alone. 1 Given the dismal mortality associated with pancreatic cancer, much attention has been given to the prevention of this deadly disease. Several risk factors have been identified with the aim of minimizing these factors for the purpose of prevention.Obesity is one such risk factor, which has been shown to increase the risk for pancreatic cancer in numerous prospective cohort studies. A body mass index (BMI) !30 was found to increase relative risk (RR) for pancreatic adenocarcinoma, with RR values ranging between 1.2 and 2.76. [2][3][4][5][6] However, the exact mechanisms that relate obesity to pancreatic cancer continue to be investigated.Fatty acid metabolism is an area of research that may help explain the tie between obesity and pancreatic cancer. Our lab previously found that omega-3 fatty acids have a chemopreventive role against the development of pancreatic neoplasia in a murine model. 7 In contrast, previous studies have shown that diets rich in x-6 fatty acids stimulated pancreatic tumor growth, in vitro and in vivo. 8,9 However, these studies have had conflicting explanations for mechanism. In vitro evidence argued for increased proliferation rates due to x-6 fatty acids while in vivo studies found no difference in proliferation rates. Furthermore, nearly all related animal studies utilized carcinogen-induced invasive pancreatic adenoc...

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Section: Resultsmentioning

confidence: 78%

“…Halberg et al . illustrated the effects of genetic background on an intestinal polyposis model that also developed pancreatic adenocarcinoma (primarily, though not exclusively, acinar in histotype) 13. Mice of 129 and (B6 X 129) F1 backgrounds were mutated for Apc and p 53( Apc Min/+ p 53 −/− ).…”

Section: Discussionmentioning

confidence: 99%

Alteration of strain background and a high omega‐6 fat diet induces earlier onset of pancreatic neoplasia in EL‐Kras transgenic mice

Cheon

Strouch

Barron

et al. 2010

Intl Journal of Cancer

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“…Potential roles of genetic or environmental factors have been extensively investigated with these models. For instance, disruption of p53 (9,10) or phosphatase and tensin homolog deleted from chromosome 10 (PTEN) (11,12) or induction of oncogenic Kras (13-15) significantly promoted intestinal tumorigenesis only in the context of APC loss. Protumorigenic effects by active inflammation have been demonstrated by inducing colitis with dextran sodium sulfate (DSS) (16).…”

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confidence: 99%

Genetic reconstitution of tumorigenesis in primary intestinal cells

Onuma¹,

Ochiai²,

Orihashi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

103

105

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Animal models for human colorectal cancer recapitulate multistep carcinogenesis that is typically initiated by activation of the Wnt pathway. Although potential roles of both genetic and environmental modifiers have been extensively investigated in vivo, it remains elusive whether epithelial cells definitely require interaction with stromal cells or microflora for tumor development. Here we show that tumor development could be simply induced independently of intestinal microenvironment, even with WT murine primary intestinal cells alone. We developed an efficient method for lentiviral transduction of intestinal organoids in 3D culture. Despite seemingly antiproliferative effects by knockdown of adenomatous polyposis coli (APC), we managed to reproducibly induce APC-inactivated intestinal organoids. As predicted, these organoids were constitutively active in the Wnt signaling pathway and proved tumorigenic when injected into nude mice, yielding highly proliferative tubular epithelial glands accompanied by prominent stromal tissue. Consistent with cellular transformation, tumor-derived epithelial cells acquired sphere formation potential, gave rise to secondary tumors on retransplantation, and highly expressed cancer stem cell markers. Inactivation of p53 or phosphatase and tensin homolog deleted from chromosome 10, or activation of Kras, promoted tumor development only in the context of APC suppression, consistent with earlier genetic studies. These findings clearly indicated that genetic cooperation for intestinal tumorigenesis could be essentially recapitulated in intestinal organoids without generating gene-modified mice. Taken together, this in vitro model for colon cancer described herein could potentially provide unique opportunities for carcinogenesis studies by serving as a substitute or complement to the currently standard approaches.colon carcinogenesis | shRNA | primary culture | Matrigel | validation

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“…While the APC gene has been identified to be one of the most important genes that play a role in the development of colorectal cancer, there are multiple proteins that work in parallel with Apc to create these cancers (Sjöblom et al, 2006;Wood et al, 2007). Although the actual mechanisms of selection are not clear, it is known that proteins which are not directly interacting with APC, and have similar functions in a cell-such as tumor suppressor genes PTEN (Marsh et al, 2008), TRP53 (Halberg et al, 2008), and p21 …”

Section: Introductionmentioning

confidence: 99%

Vavien: An Algorithm for Prioritizing Candidate Disease Genes Based on Topological Similarity of Proteins in Interaction Networks

Erten

Bebek

Koyutürk

2011

Journal of Computational Biology

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Genome-wide linkage and association studies have demonstrated promise in identifying genetic factors that influence health and disease. An important challenge is to narrow down the set of candidate genes that are implicated by these analyses. Protein-protein interaction (PPI) networks are useful in extracting the functional relationships between known disease and candidate genes, based on the principle that products of genes implicated in similar diseases are likely to exhibit significant connectivity/proximity. Information flow-based methods are shown to be very effective in prioritizing candidate disease genes. In this article, we utilize the topology of PPI networks to infer functional information in the context of disease association. Our approach is based on the assumption that PPI networks are organized into recurrent schemes that underlie the mechanisms of cooperation among different proteins. We hypothesize that proteins associated with similar diseases would exhibit similar topological characteristics in PPI networks. Utilizing the location of a protein in the network with respect to other proteins (i.e., the ''topological profile'' of the proteins), we develop a novel measure to assess the topological similarity of proteins in a PPI network. We then use this measure to prioritize candidate disease genes based on the topological similarity of their products and the products of known disease genes. We test the resulting algorithm, Vavien, via systematic experimental studies using an integrated human PPI network and the Online Mendelian Inheritance in Man (OMIM) database. Vavien outperforms other network-based prioritization algorithms as shown in the results and is available at www.diseasegenes.org.

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The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

Cited by 13 publications

References 58 publications

Alteration of strain background and a high omega‐6 fat diet induces earlier onset of pancreatic neoplasia in EL‐Kras transgenic mice

Alteration of strain background and a high omega‐6 fat diet induces earlier onset of pancreatic neoplasia in EL‐Kras transgenic mice

Genetic reconstitution of tumorigenesis in primary intestinal cells

Vavien: An Algorithm for Prioritizing Candidate Disease Genes Based on Topological Similarity of Proteins in Interaction Networks

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