Colonic Neoplasms in Mice Produced with Six Injections of 1,2-Dimethylhydrazine

Long, Florence C.

doi:10.1159/000225236

Cited by 37 publications

(14 citation statements)

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“…DMH was used to induce colonic tumours in wild‐type, heterozygous K‐ ras tm Δ4 A /+ and homozygous K‐ ras tm Δ4 A / tm Δ4 A mice. Although activating K‐ ras mutations have sometimes been detected in DMH‐induced bowel tumours in the rat model 25, they were not detected in colonic adenomas in mouse models investigated here or elsewhere 26–28. K‐ ras tm Δ4 A / tm Δ4 A mice exhibit normal life expectancy and an overall similar spontaneous tumour incidence to that of wild‐type mice 16, indicating that K‐ ras tm Δ4 A / tm Δ4 A mice provide an excellent experimental model to explore the effects of K‐ ras 4A and 4B isoforms on colonic tumourigenesis.…”

Section: Introductionmentioning

confidence: 76%

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K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

Luo

Hamoudi

et al. 2010

The Journal of Pathology

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K-ras encodes two isoforms, K-ras 4A and 4B, that are jointly affected by K-ras activating mutations, which are prevalent in colorectal cancer (CRC). CRC shows alterations in the expressed K-ras 4A : 4B isoform ratio in favour of K-ras 4B, in tumours both with and without K-ras mutations. The present study evaluated whether K-ras 4A expression can suppress colonic adenoma development in the absence of its oncogenic allele. Mice with homozygous targeted deletions of K-ras exon 4A (K-ras(tmDelta4A/tmDelta4A)) that can express the K-ras 4B isoform only, along with heterozygous K-ras(tmDelta4A/+) and wild-type mice, were given ten weekly 1,2-dimethylhydrazine (DMH) treatments to induce colonic adenomas. There was a significant increase in both the number and the size of colonic adenomas in DMH-treated K-ras(tmDelta4A/tmDelta4A) mice, with reduced survival, compared with heterozygous and wild-type mice. No K-ras mutations were found in any of the 30 tumours tested from the three groups. Lack of expression of K-ras 4A transcripts was confirmed, whereas the relative expression levels of K-ras 4B transcripts were significantly increased in the adenomas of K-ras(tmDelta4A/tmDelta4A) mice compared with K-ras(tmDelta4A/+) and wild-type mice. Immunohistochemical studies showed that adenomas of K-ras(tmDelta4A/tmDelta4A) mice had significantly increased cell proliferation and significantly decreased apoptosis with evidence of activation of MapKinase and Akt pathways, with increased phospho-Erk1/2 and both phospho-Akt-Thr308 and phospho-Akt-Ser473 immunostaining, compared with adenomas from K-ras(tmDelta4A/+) and wild-type mice. In conclusion, following DMH treatment, K-ras exon 4A deletion promoted increased number and size of colonic adenomas showing increased K-ras 4B expression, increased proliferation, decreased apoptosis, and activation of MapKinase and Akt pathways, in the absence of K-ras mutations. Therefore, K-ras 4A expression had a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation, explaining the selective advantage of the altered K-ras 4A : 4B isoform ratio found in human colorectal cancer.

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Section: Introductionmentioning

confidence: 76%

“…DMH·2HCl (2.0 mg/ml) was dissolved in 0.90% saline containing 1 m M EDTA and 10 m M sodium citrate, and the pH was adjusted to 6.5 using 0.5 M NaOH. Previously validated DMH treatments consisted of ten weekly injections of 20.0 mg/kg, starting at age 7–8 weeks (cumulative dose = 200.0 mg/kg DMH·2HCl or 145.0 mg/kg DMH) 26–28.…”

Section: Methodsmentioning

confidence: 99%

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

Luo

Hamoudi

et al. 2010

The Journal of Pathology

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“…In the earliest published studies repetitive administration of DMH in rodents was demonstrated to induce colon tumors with pathological features similar to that seen in sporadic human disease,[2627] Later studies switched to AOM,[28–30] due to practical advantages such as reproducibility, high potency, simple mode of application, excellent stability in solution, and low price. [29]…”

Section: Experimental Colon Carcinogenesis In Rodentsmentioning

confidence: 99%

The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

et al. 2011

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Colorectal cancer (CRC) is a major health problem in industrialized countries. Although inflammation-linked carcinogenesis is a well accepted concept and is often observed within the gastrointestinal tract, the underlying mechanisms remain to be elucidated. Inflammation can indeed provide initiating and promoting stimuli and mediators, generating a tumour-prone microenvironment. Many murine models of sporadic and inflammation-related colon carcinogenesis have been developed in the last decade, including chemically induced CRC models, genetically engineered mouse models, and xenoplants. Among the chemically induced CRC models, the combination of a single hit of azoxymethane (AOM) with 1 week exposure to the inflammatory agent dextran sodium sulphate (DSS) in rodents has proven to dramatically shorten the latency time for induction of CRC and to rapidly recapitulate the aberrant crypt foci–adenoma–carcinoma sequence that occurs in human CRC. Because of its high reproducibility and potency, as well as the simple and affordable mode of application, the AOM/DSS has become an outstanding model for studying colon carcinogenesis and a powerful platform for chemopreventive intervention studies. In this article we highlight the histopathological and molecular features and describe the principal genetic and epigenetic alterations and inflammatory pathways involved in carcinogenesis in AOM/DSS–treated mice; we also present a general overview of recent experimental applications and preclinical testing of novel therapeutics in the AOM/DSS model.

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“…), but for DMH‐treated mice, K‐ ras mutations in adenomas are much less common or rare, although DMH is known to induce intestinal adenoma formation by either activating Beta ‐ Catenin mutations or inactivating Apc mutations (Jackson et al . ; Deschner & Long ; Deschner et al . ; Diwan et al .…”

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confidence: 99%

Wild‐type K‐ras has a tumour suppressor effect on carcinogen‐induced murine colorectal adenoma formation

Luo

Poulogiannis

et al. 2013

Int J Experimental Path

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K-ras mutations are found in ~40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras(+/+) ) and heterozygous K-ras exon 1 knockout (K-ras(+/-) ) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras(+/-) mice were ~50% decreased compared with K-ras(+/+) mice. One year after DMH treatment, survival of K-ras(+/-) mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras(+/+) mice to 0.87 ± 0.14 in K-ras(+/-) mice (mean ± SEM per mouse, P < 0.01); total tumour volume increased 2.13-fold (P < 0.05). Comparing K-ras(+/+) with K-ras(+/-) murine adenomas, Ki-67-positive proliferating tumour cells significantly increased from 7.77 ± 0.64% to 9.15 ± 0.92% and cleaved caspase-3-positive apoptotic tumour cells decreased from 1.40 ± 0.37% to 0.80 ± 0.22% (mean ± SEM, P < 0.05 for both). No K-ras or B-raf mutations were detected in the adenomas. Immunohistochemical studies showed no significant changes in extracellular signal regulating kinase/mitogen-activated protein kinase (Erk/MapK) or PI3K/Akt pathway activation in the adenomas. In conclusion, the data collectively show that a 50% reduction in K-ras gene dosage and RNA expression promoted experimental colorectal tumourigenesis, consistent with wild-type K-ras having a tumour suppressor effect on carcinogen-induced murine colorectal adenoma formation.

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Colonic Neoplasms in Mice Produced with Six Injections of 1,2-Dimethylhydrazine

Cited by 37 publications

References 6 publications

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies

Wild‐type K‐ras has a tumour suppressor effect on carcinogen‐induced murine colorectal adenoma formation

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