Myh
 Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia (
 Apc
 
 
 Min
 /+) Mice

Sieber, Oliver M.; Howarth, Kimberley; Thirlwell, Christina; Rowan, Andrew; Mandir, Nikki; Goodlad, R A; Gilkar, Ashfaq; Spencer‐Dene, Bradley; Stamp, Gordon W.; Johnson, Victoria L.; Silver, Andrew; Yang, Hanjing; Miller, Jeffrey H; Ilyas, Mohammad; Tomlinson, Ian

doi:10.1158/0008-5472.can-04-2958

Cited by 47 publications

(25 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The correlative changes in LOH status at the Apc locus observed in normal MIN mice, as well as in MIN/SSAT-tg and MIN/ SSAT-ko mice, is highly supportive of the above paradigm. The idea that the LOH may be due to increased DNA damage caused by reactive by-products of polyamine oxidase is quite consistent with several studies showing that MIN mice having deficiencies in DNA repair manifest similar increases in intestinal tumor development (43)(44)(45)(46). The consequences of altered metabolic flux through the polyamine pathways are obviously very different between the intestinal tract and the prostate of the mouse.…”

Section: Discussionsupporting

confidence: 81%

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Tucker

Murphy²,

Kisiel³

et al. 2005

Cancer Research

View full text Add to dashboard Cite

Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc Min/+ (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3-and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N 1 -acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers. (Cancer Res 2005; 65(12): 5390-8)

show abstract

Section: Discussionsupporting

confidence: 81%

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Tucker

Murphy²,

Kisiel³

et al. 2005

Cancer Research

View full text Add to dashboard Cite

show abstract

“…Microsatellite PCR was performed by using standard laboratory procedures. Loss of heterozygosity analysis of Apc alleles was conducted as described by Sieber et al (22). Research Council, Harwell, U.K.).…”

Section: Methodsmentioning

confidence: 99%

Genetic basis of variation in adenoma multiplicity in Apc ^{Min
/+} Mom1 ^S mice

Haines

Johnson

Pack

et al. 2005

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

Self Cite

View full text Add to dashboard Cite

. FAP patients inherit a mutated copy of the adenomatous polyposis coli (APC) gene (1-3), whereas hereditary nonpolyposis CRC is caused by inheritance of defective DNA mismatch repair genes such as MSH2 or MLH1 (4, 5). However, hereditary nonpolyposis CRC and FAP account for only a small fraction of the colorectal tumors presenting in the human population. The vast majority of CRCs (Ϸ80%) do not result from a known inherited factor, are considered sporadic in origin, and demonstrate somatic mutation of the APC gene (6-10).Many studies have suggested a role for uncharacterized genetic factors in predisposition to the common forms of colorectal tumors. Thus, relatives of CRC patients are at an increased risk of the disease, and segregation analysis has suggested dominant inheritance of CRC susceptibility (11,12). In addition, an extensive analysis of twins showed that up to one-third of CRCs may have some inherited basis (13). The remaining, uncharacterized predisposition to CRC in humans is more likely to be the result of several genes of low-penetrance rather than highpenetrance mutations at single loci with large effects on risk (14). Much of the risk of CRC may result from a primary predisposition to colorectal adenomas. The number of colorectal adenomas presenting within FAP families or individuals with identical germ-line APC mutations has been shown to vary, suggesting that hereditary factors also may influence disease severity (15). The same genes that modify the phenotype of individuals with FAP also may influence the risk of CRC in the general population. A search for FAP modifier genes, either directly or through rodent models, therefore may lead to the identification of important susceptibility genes for human CRC.The first mouse model used to study the involvement of the Apc gene in CRC is referred to as Min (Multiple intestinal neoplasia). Apc Min/ϩ (Min) mice are heterozygous for a truncating Apc mutation and develop numerous intestinal adenomas, thereby providing a good model of human FAP. The Min model has been used to provide an unambiguous example of a modifying locus in mice. A single locus was identified as a consequence of significant variation in the polyp number, depending on the inbred mouse strain harboring the Apc mutation. Linkage analysis located Mom1 on mouse chromosome 4, and further analysis identified the secretory phospholipase A2 (Pla2g2a) as a candidate gene (16)(17)(18). Unfortunately, studies in humans did not confirm PLA2G2A as a major modifier of colorectal cancer risk in humans because functional polymorphic variation did not exist (19,20). A second locus, Mom2, on distal chromosome 18 was identified by Silverman et al. (21), although the underlying genetic defect has yet to be established. We now have direct evidence of a further Mom locus controlling susceptibility to a particularly severe form of intestinal disease in Min mice. Materials and MethodsHusbandry. Mice were housed in conventional cages, and a standard maintenance diet was provided ad libitum. All procedures i...

show abstract

“…14). Myh-deficient mice are more susceptible to spontaneous tumors either alone (15,16) or in combination with 8-oxoguanine DNA glycosylase 1 (Ogg1) deficiency (17). Myh-deficient mice were also found to be susceptible to oxidative stress-induced intestinal tumors (15).…”

Section: Introductionmentioning

confidence: 99%

DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

Meira¹,

Bugni²,

Green³

et al. 2008

J. Clin. Invest.

376

419

View full text Add to dashboard Cite

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

show abstract

Myh Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia ( Apc Min /+) Mice

Abstract: ABSTRACT

Cited by 47 publications

References 36 publications

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Genetic basis of variation in adenoma multiplicity in Apc ^{Min
/+} Mom1 ^S mice

DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

Contact Info

Product

Resources

About

Myh Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia ( Apc Min /+) Mice

Abstract: ABSTRACT

Cited by 47 publications

References 36 publications

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Genetic basis of variation in adenoma multiplicity in Apc Min /+ Mom1 S mice

DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

Contact Info

Product

Resources

About

Genetic basis of variation in adenoma multiplicity in Apc ^{Min
/+} Mom1 ^S mice